EP2381960A1

EP2381960A1 - Stable pharmaceutical composition containing at least one monoclonal antibody and at least one amphiphilic polysaccharide comprising hydrophobic substituents

Info

Publication number: EP2381960A1
Application number: EP09805833A
Authority: EP
Inventors: Olivier Soula; Gérard Soula; Martin Gaudier; Rémi SOULA
Original assignee: Adocia SAS
Current assignee: Adocia SAS
Priority date: 2008-12-23
Filing date: 2009-12-23
Publication date: 2011-11-02
Also published as: FR2944448A1; CN102300586A; CA2748069A1; FR2944448B1; JP2012513456A; AU2009332642A1; US20110014189A1; WO2010073119A1; IL213682A0

Abstract

The invention relates to a stable pharmaceutical composition containing at least one monoclonal antibody and at least one amphiphilic polysaccharide selected from the group of amphiphilic polysaccharides comprising carboxyl functional groups partially substituted by at least one hydrophobic substituent. According to the invention, the amphiphilic polysaccharide is selected from polysaccharides containing functional carboxyl groups, at least one of which is substituted by a hydrophobic radical noted Hy: ° said hydrophobic radical (HY) being grafted or bonded to the anionic polysaccharide either: - by an F' function, the F' function resulting from the linking of a reactive function of a hydrophobic compound to a carboxyl function of the anionic polysaccharide; by a linking arm R, said linking arm R being bonded to the polysaccharide by a bond F resulting from the linking of a reactive function of the R' linking arm precursor to a carboxyl function of the anionic polysaccharide, and said hydrophobic radical (Hy) being bonded to the R-linking arm by a function G resulting from the linking of a reactive function of a hydrophobic compound to a reactive function of the R' linking arm precursor; ° the non-substituted carboxyl functions of the anionic polysaccharide being in the form of a cation carboxylate, preferably an alkaline such as Na+ or K+; ° F being an amide, ester, thioester or anhydride function; ° F' being an amide, ester, thioester or anhydride function; ° G being an amide, ester, thioester, thionoester carbamate, carbonate or anhydride function; ° Hy being a radical resulting from the linking of reactive function of a hydrophobic compound to a carboxyl function of the anionic polysaccharide or from the linking of a reactive function of a hydrophobic compound to a reactive function of the R' linking arm precursor, made of a chain containing 4 to 50 carbon atoms and optionally branched and/or unsaturated, optionally including one or more heteroatoms such as O, N and/or S, optionally including one or more saturated, unsaturated or aromatic cycles or heterocycles; R being a divalent radical comprising a chain including 1 to 18 carbon atoms, optionally branched and/or unsaturated, optionally including one or more heteroatoms such as O, N and/or S, optionally including one or more saturated, unsaturated or aromatic cycles or heterocycles and resulting from the reaction of an R' precursor having at least identical or different reactive functions selected from the group comprising alcohol, acid, amino, thiol and thioacid functions; ° wherein said polysaccharide including functional carboxyl groups is amphiphilic at a neutral pH.

Description

A stable pharmaceutical composition comprising at least one monoclonal antibody and at least one amphiphilic polysaccharide comprising hydrophobic substituents.

[0001] Monoclonal Antibodies have been in recent years a thundering success due to their exceptional effectiveness in treating certain cancers and a certain number of chronic diseases affecting a large number of patients. These diseases include various forms of cancer, prostate cancer, breast cancer, liver cancer, but also other diseases such as rheumatic arthritis, certain infectious diseases, age-related macular degeneration. etc.

Some compounds of this family are already reference drugs for these conditions. The therapeutic interest of Monoclonal Antibodies being established, many biopharmaceutical companies are engaged in the development of new compounds, which may have greater therapeutic effects while having lesser side effects. However, these Monoclonal Antibodies must be, for the most part, administered in large quantities in order to achieve the desired therapeutic effect.

A major difficulty consists in obtaining pharmaceutical compositions containing the necessary amount of protein, with sufficient storage stability to ensure its effectiveness over time and avoid the formation of byproducts that could have effects side effects, in particular immunogenic effects.

Indeed, it is observed that these Monoclonal Antibodies, which are high molecular weight proteins, are easily aggregated under the effect of temperature or mechanical stress. This is observed, including on products such as Avastin and Erbitux, which are currently marketed. Their use requires filtration before use, in order to remove the precipitated particles. It is obvious that under these conditions, the amount of active ingredient administered as well as the nature and amount of impurities that are not filtered can not be controlled. Many attempts have been made to obtain stable pharmaceutical compositions of monoclonal antibodies at high concentrations. [0008] For example:

CHUGAI application NZ534542 which relates to stable formulations of anti-interleukin 6 or anti-HM1.24 receptor antibodies, which contain a sugar as a stabilizer, said sugar being a non-reducing sugar, disaccharide or trisaccharide,

the application WO2006 / 044908 in the name of GENENTECH which describes stable formulations of monoclonal antibodies in a histidine buffer, said formulations being capable of including, inter alia, disaccharides, in particular trehalose and sucrose. the application WO2008 / 121615 in the name of Medimune, which relates to anti-interferon antibody formulations, said formulations comprising, inter alia, a buffering buffer of histidine citrate, etc. but also trehalose or sucrose. Much of the work done is limited to seek, for a given antibody, an effective buffer for the conservation of biological activity. Solutions provided on a case by case basis are therefore not generalizable and, what is more, often prove ineffective as can be observed for many commercial products.

The present invention solves the problem of stability of monoclonal antibodies by the use of polysaccharides simultaneously comprising carboxylate groups and hydrophobic substituents. In particular, the Applicant has demonstrated that said modified polysaccharides simultaneously comprising carboxylate and hydrophobic groups:

- stabilize the antibodies, with respect to aggregation and precipitation

- increase the solubility, - help solubilization.

The present invention solves, in general, the stability problems of monoclonal antibodies. It relates to a stable pharmaceutical composition comprising at least one monoclonal antibody and at least one amphiphilic polysaccharide.

For example, a stable composition will be a composition comprising a monoclonal antibody and an amphiphilic polysaccharide in no aggregation is detected after incubation for 48 hours at 56 ° C in aqueous solution at the use concentration.

In one embodiment, the amphiphilic polysaccharide is chosen from polysaccharides comprising carboxyl functional groups, at least one of which is substituted with at least one hydrophobic radical, denoted by Hy:

Said hydrophobic radical (Hy) being grafted or bonded to the anionic polysaccharide:

by a function F ', said function F' resulting from the coupling between a reactive function of a hydrophobic compound and a carboxyl function of the anionic polysaccharide,

by a linker R, said linker R being linked to the polysaccharide by a link F resulting from the coupling between a reactive function of the precursor of the linker arm R 'and a carboxyl function of the anionic polysaccharide and said hydrophobic radical (Hy) being linked to the linker R by a function G resulting from the coupling between a reactive function of a hydrophobic compound and a reactive function of the precursor of the linking arm R '.

The carboxyl functions of the unsubstituted anionic polysaccharide being in the form of a cation carboxylate, preferably alkaline, such as Na ⁺ or K ⁺ .

F being either an amide, ester, thioester or anhydride function,

F 'being either an amide, ester, thioester or anhydride function,

G being either an amide, ester, thioester, thionoester carbamate, carbonate or anhydride function, where Hy is a radical resulting either from the coupling between a reactive functional group of a hydrophobic compound and a carboxyl function of the anionic polysaccharide, or from the coupling between a reactive function of a hydrophobic compound and a reactive function of the precursor of the linking arm R '. consisting of a chain comprising between 4 and 50 carbons, optionally branched and / or unsaturated, optionally comprising one or more heteroatoms, such as O, N or / and S, optionally comprising one or more saturated, unsaturated or aromatic rings or heterocycles,

R being a divalent radical consisting of a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated, optionally comprising one or more heteroatoms, such as O, N or / and S, optionally comprising one or more saturated, unsaturated or aromatic rings or heterocycles and resulting from the reaction of a precursor R 'having at least two reactive functions, which are identical or different from the group consisting of alcohol, acid, amine, thiol and thioacid functions.

Said polysaccharide comprising carboxyl functional groups being amphiphilic at neutral pH.

In one embodiment, the polysaccharides comprising carboxyl functional groups are polysaccharides naturally carrying carboxyl functional groups and are chosen from the group consisting of alginate, hyaluronan and galacturonan.

In one embodiment, the polysaccharides comprising carboxyl functional groups are synthetic polysaccharides obtained from polysaccharides naturally comprising carboxyl functional groups or from neutral polysaccharides, in which at least 15 carboxyl functional groups per 100 saccharide units. have been grafted, of general formula I.

the natural polysaccharides being chosen from the group of polysaccharides consisting mainly of glycoside monomers linked by glycoside bonds of (1,6) and / or (1,4) and / or (1,3) and / or (1) , 2),

L being a bond resulting from the coupling between the linker Q and an OH function of the polysaccharide and being either an ester, thionoester, carbonate, carbamate or ether function,

i represents the mole fraction of the L-Q substituents per saccharide unit of the polysaccharide

Q being a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, IM or / and S, and having at least one carboxyl functional group, -CO ₂ H.

In one embodiment, the polysaccharide consists mainly of glycoside monomers linked by glycoside bonds of (1,6) type.

In one embodiment, the polysaccharide consisting predominantly of glycoside monomers linked by glycoside bonds of (1,6) type is dextran. In one embodiment, the polysaccharide consists predominantly of glycoside monomers linked by glycoside bonds of (1,4) type.

In one embodiment, the polysaccharide consisting predominantly of glycoside monomers linked by glycoside bonds of (1,4) type is selected from the group consisting of pullulan, alginate, hyaluronan, xylan, galacturonan or a water-soluble cellulose.

In one embodiment, the polysaccharide is a pullulan.

In one embodiment, the polysaccharide is an alginate.

In one embodiment, the polysaccharide is a hyaluronan. In one embodiment, the polysaccharide is a xylan.

In one embodiment, the polysaccharide is a galacturonan.

In one embodiment, the polysaccharide is a water-soluble cellulose.

In one embodiment, the polysaccharide consists mainly of glycoside monomers linked by glycoside bonds of (1,3) type.

In one embodiment, the polysaccharide consisting predominantly of glycoside monomers linked by glycoside bonds of (1,3) type is a curdlane. In one embodiment, the polysaccharide consists predominantly of glycoside monomers linked by glycoside bonds of (1,2) type.

In one embodiment, the polysaccharide consisting predominantly of glycoside monomers linked by glycoside bonds of (1,2) type is an inulin.

In one embodiment, the polysaccharide consists mainly of glycoside monomers linked by glycoside bonds of (1,4) and (1,3) type. In one embodiment, the polysaccharide consisting predominantly of glycoside monomers linked by glycoside bonds of (1,4) and (1,3) type is a glucan.

In one embodiment, the polysaccharide consists mainly of glycoside monomers linked by glycoside bonds of (1,4), and (1,3) and (1,2) type.

In one embodiment, the polysaccharide consists mainly of glycoside monomers linked by glycoside bonds of (1,4) type, and (1,3) and (1,2) is mannan.

In one embodiment, the polysaccharide according to the invention is characterized in that the Q group is chosen from the following groups:

In one embodiment, i is between 0.1 and 3. [00037] In one embodiment, i is between 0.2 and 1.5.

In one embodiment, the polysaccharides are polysaccharides comprising carboxyl functional groups of which at least one is substituted with a hydrophobic alcohol derivative, denoted by Ah:

Said hydrophobic alcohol (Ah) being grafted or bound to the anionic polysaccharide by a coupling arm R, said coupling arm being linked to the anionic polysaccharide by a function F, said function resulting from the coupling between an amine, alcohol, thioalcohol or carboxyl function; of the precursor of the linker R 'and a carboxyl function of the anionic polysaccharide, and said coupling arm R being linked to the hydrophobic alcohol by a function G resulting from the coupling between a carboxyl, amine, thioacid or alcohol function of the precursor of the arm R 'coupling and an alcohol function of the hydrophobic alcohol, the carboxyl functions of the unsubstituted anionic polysaccharide being in the form of cation carboxylate, alkali preferably as Na ⁺ or K ⁺ . F being either an amide function or an ester function or a thioester function or an anhydride function

- G being either an ester function or a thioester function, or a carbonate function, or a carbamate function, - R being a divalent radical consisting of a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated, optionally comprising one or more heteroatoms, such as O, N or / and S,

- Ah being a residue of a hydrophobic alcohol or thioalcohol, product of the coupling between the hydroxyl function of the hydrophobic alcohol and at least one reactive function carried by the precursor of the divalent radical R,

In one embodiment, F is an amide function, G is an ester function, R 'is an amino acid and Ah is a hydrophobic alcohol residue.

In one embodiment, F is an amide function, G is a thioester function, R 'is an amino acid and Ah is a hydrophobic thioalcohol residue.

In one embodiment, F is an amide function, G is a carbamate function, R 'is a diamine and Ah is a hydrophobic alcohol residue.

In one embodiment, F is an amide function, G is a carbonate function, R 'is an aminoalcohol and Ah is a hydrophobic alcohol residue.

In one embodiment, F is an amide function, G is a thionoester function, R 'is an O-thioacideaminé and Ah is a hydrophobic alcohol residue. In one embodiment, F is an ester function, G is an ester function, R 'is an acid alcohol, and Ah is a hydrophobic alcohol residue.

In one embodiment, F is an ester function, G is a thioester function, R 'is an acidealcool and Ah is a hydrophobic thioalcohol residue. In one embodiment, F is an ester function, G is a carbonate function, R 'is a dialcohol and Ah is a hydrophobic alcohol residue. In one embodiment, F is an ester function, G is a carbamate function, R 'is an alcoholamine and Ah is a hydrophobic alcohol residue.

In one embodiment, F is a thioester function, G is an ester function, R 'is an acid thiol, and Ah is a hydrophobic alcohol residue.

In one embodiment, F is a thioester function, G is a thioester function, R 'is an acid thiol and Ah is a hydrophobic thioalcohol residue.

In one embodiment, F is a thioester function, G is a carbonate function, R 'is an alcohol thiol and Ah is a hydrophobic alcohol residue.

In one embodiment, F is a thioester function, G is a carbamate function, R 'is an aminethiol and Ah is a hydrophobic alcohol residue. In one embodiment, F is an anhydride function, G is an ester function, R 'is a diacid and Ah is a hydrophobic alcohol residue.

In one embodiment, F is an anhydride function, G is a thioester function, R 'is a diacid and Ah is a hydrophobic thioalcohol residue. In one embodiment, F is an anhydride function, G is a carbamate function, R 'is an amino acid and Ah is a hydrophobic alcohol residue.

In one embodiment, F is an anhydride function, G is a carbonate function, R 'is an acid alcohol, and Ah is a hydrophobic alcohol residue.

In one embodiment, said polysaccharide comprising carboxyl functional groups partially substituted by hydrophobic alcohols is chosen from polysaccharides comprising carboxyl functional groups of general formula II:

Formula II

in which n represents the mole fraction of the carboxyl functions of the polysaccharide substituted with F-R-G-Ah and is between

0.01 and 0.7,

- F, R, G and Ah as defined above, and when the carboxyl function of the polysaccharide is not substituted by FRG-Ah, then the carboxyl functional group (s) of the polysaccharide are cation carboxylates, alkali preferably as Na ⁺ or K ⁺ .

In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from amino acids.

In one embodiment, the amino acids are chosen from alpha amino acids.

In one embodiment, the alpha amino acids are chosen from alpha natural amino acids.

In one embodiment, the natural alpha amino acids are chosen from leucine, alanine, iso-leucine, glycine, phenylalanine, tryptophan, valine and proline.

In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from polyols.

In one embodiment, the polyols are chosen from dialcohols. In one embodiment, the dialcohols are selected from the group consisting of diethylene glycol and triethylene glycol. In one embodiment, the dialcohols are chosen from the group consisting of polyethylene glycols without any restriction of mass. In one embodiment, the polyols are chosen from the group consisting of glycerol, diglycerol and triglycerol. In one embodiment, the polyol is triethanolamine.

In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from diamines.

In one embodiment, the diamines are chosen from the group consisting of ethylene diamine and lysine and its derivatives.

In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from alcoholamines.

In one embodiment, the alcoholamines are chosen from the group consisting of ethanolamine, 2-aminopropanol, isopropanolamine, 3-amino-1,2-propanediol, diethanolamine and diisopropanolamine. , tromethamine (Tris) and 2- (2-aminoethoxy) ethanol. In one embodiment, the alcoholamines are selected from the group consisting of reduced amino acids.

In one embodiment, the reduced amino acids are chosen from the group consisting of alaninol, valinol, leucinol, isoleucinol, prolinol and phenylalaninol. In one embodiment, the alcoholamines are selected from the group consisting of charged amino acids.

In one embodiment, the charged amino acids are selected from the group consisting of serine and threonine.

In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from diacids.

In one embodiment, the diacid is selected from the group consisting of succinic acid, glutamic acid, maleic acid, oxalic acid, malonic acid, fumaric acid and the like. glutaconic acid.

In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from the acid alcohols. In one embodiment, the alcoholic acids are chosen from the group consisting of mandelic acid, lactic acid and citric acid.

In one embodiment, the hydrophobic alcohol is chosen from fatty alcohols.

In one embodiment, the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising from 4 to 18 carbons. In one embodiment, the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising from 6 to 18 carbons.

In one embodiment, the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising more than 18 carbons.

In one embodiment, the hydrophobic alcohol is octanol. In one embodiment, the hydrophobic alcohol is dodecanol.

In one embodiment, the hydrophobic alcohol is 2-ethylbutanol.

In one embodiment, the fatty alcohol is selected from meristyl, cetyl, stearyl, cetearyl, butyl, oleyl and lanolin. In one embodiment, the hydrophobic alcohol is chosen from cholesterol derivatives.

In one embodiment, the cholesterol derivative is cholesterol.

In one embodiment, the hydrophobic alcohol is chosen from menthol derivatives.

In one embodiment, the hydrophobic alcohol is menthol in its racemic form,

In one embodiment, the hydrophobic alcohol is the D-isomer of menthol. In one embodiment, the hydrophobic alcohol is the L isomer of menthol.

In one embodiment, the hydrophobic alcohol is chosen from tocopherols. [00095] In one embodiment, the tocopherol is alpha tocopherol.

In one embodiment, alpha tocopherol is the racemic alpha tocopherol.

In one embodiment, the tocopherol is the D isomer of alpha tocopherol.

In one embodiment, the tocopherol is the L isomer of alpha tocopherol.

In one embodiment, the hydrophobic alcohol is chosen from alcohols bearing an aryl group. In one embodiment, the aryl group-bearing alcohol is chosen from benzyl alcohol and phenethyl alcohol.

In one embodiment, the hydrophobic alcohol is chosen from unsaturated fatty alcohols in the group consisting of geraniol, β-citronellol and farnesol. [000102] In one embodiment, the hydrophobic alcohol is 3,7-dimethyl-1-octanol.

In one embodiment, the polysaccharides are polysaccharides comprising carboxyl functional groups in which at least one of said carboxyl groups is substituted by a hydrophobic alcohol derivative, denoted by Ah:

Said hydrophobic alcohol (Ah) being grafted or bound to the anionic polysaccharide by a function F ', said function F' resulting from the coupling between the carboxylate function of the anionic polysaccharide and the hydroxyl function of the hydrophobic alcohol, the carboxyl functions of the unsubstituted anionic polysaccharide being in the form of a cation carboxylate, preferably alkaline, such as Na ⁺ or K ⁺ .

F 'being an ester or thioester function,

• Ah being a residue of a hydrophobic alcohol, or hydrophobic thioalcohol, • said polysaccharide having carboxyl functional groups being amphiphilic at neutral pH. In one embodiment, the polysaccharide comprising carboxyl functional groups partially substituted with hydrophobic alcohols is chosen from polysaccharides comprising carboxyl functional groups of general formula III: embedded image

Polysaccharide + carboxyl

F ¹

Ah n

Formula III

in which n represents the mole fraction of the carboxyl functions of the polysaccharide substituted with -F'-Ah and is between 0.01 and 0.7,

Where F 'and Ah correspond to the definitions given above, and when the carboxyl function of the polysaccharide is not substituted by F'-Ah, then the carboxyl functional group (s) of the polysaccharide are cationic carboxylates, preferably alkali Na ⁺ or K ⁺ .

[000105] In one embodiment, the hydrophobic alcohol is chosen from fatty alcohols.

In one embodiment, the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising from 6 to 18 carbons.

In one embodiment, the hydrophobic alcohol is chosen from the group consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising from 8 to 18 carbons. In one embodiment, the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising more than 18 carbons.

[000109] In one embodiment, the hydrophobic alcohol is octanol.

[000110] In one embodiment, the hydrophobic alcohol is 2-ethylbutanol.

[000111] In one embodiment, the hydrophobic alcohol is dodecanol. In one embodiment, the fatty alcohol is selected from meristyl, cetyl, stearyl, cetearyl, butyl, oleyl and lanolin.

In one embodiment, the hydrophobic alcohol is chosen from cholesterol derivatives. [000114] In one embodiment, the cholesterol derivative is cholesterol.

In one embodiment, the hydrophobic alcohol is chosen from menthol derivatives.

[000116] In one embodiment, the hydrophobic alcohol is menthol in its racemic form.

In one embodiment, the hydrophobic alcohol is the D-isomer of menthol.

[000118] In one embodiment, the hydrophobic alcohol is the L-isomer of menthol. [000119] In one embodiment, the hydrophobic alcohol is selected from tocopherols.

[000120] In one embodiment, the tocopherol is alpha tocopherol.

In one embodiment, alpha tocopherol is the racemic alpha tocopherol. In one embodiment, the tocopherol is the D isomer of alpha tocopherol.

In one embodiment, the tocopherol is the L isomer of alpha tocopherol.

In one embodiment, the hydrophobic alcohol is chosen from alcohols bearing an aryl group.

In one embodiment, the aryl group-bearing alcohol is chosen from benzyl alcohol and phenethyl alcohol.

In one embodiment, the hydrophobic alcohol is selected from unsaturated fatty alcohols in the group consisting of geraniol, β-citronellol and farnesol.

[000127] In one embodiment, the hydrophobic alcohol is 3,7-dimethyl-1-octanol.

In one embodiment, the amphiphilic polysaccharides are polysaccharides comprising carboxyl functional groups, at least one of which is substituted by a hydrophobic amine derivative, noted Amh:

said hydrophobic amine being grafted or bonded to the anionic polysaccharide by an amide function F ', said amide function F' resulting from coupling between the amine function of the hydrophobic amine and a carboxyl function of the anionic polysaccharide, the carboxyl functions of the unsubstituted anionic polysaccharide being in the form of a cation carboxylate, preferably alkaline such as Na + or K +. Amh being a residue of a hydrophobic amine, product of the coupling between the amine function of the hydrophobic amine and a carboxyl functional function of the anionic polysaccharide.

In one embodiment, the polysaccharide comprising carboxyl functional groups grafted with hydrophobic amines is chosen from polysaccharides comprising carboxyl functional groups of general formula IV:

Form IV

in which n represents the molar fraction of the carboxyl functions of the polysaccharide substituted with F'-Amh and is between 0.01 and 0.7,

- F 'and Amh corresponding to the definitions given above, and when the carboxyl function of the polysaccharide is not substituted by F'-Amh, then the carboxyl function (s) of the polysaccharide are cationic carboxylates, alkali preferably as IMa + or K +.

In one embodiment, the hydrophobic amine is chosen from amines consisting of an unsaturated or saturated, branched or linear alkyl chain comprising from 6 to 18 carbons.

[000131] In one embodiment, the fatty amine is dodecylamine. In one embodiment, the fatty amine is selected from meristyl, cetyl, stearyl, cetearyl, butyl, oleyl, lanolin. In one embodiment, the hydrophobic amine is chosen from amines carrying an aryl group. In one embodiment, the amine carrying an aryl group is selected from benzylamine, the phenethyl amine.

In one embodiment, the polysaccharides are polysaccharides comprising carboxyl functional groups of which at least one of said groups is substituted by a hydrophobic acid derivative, denoted Ach: embedded image

Said hydrophobic acid (Ach) being grafted or attached to the anionic polysaccharide by an anhydride function F ', said function resulting from the coupling between the carboxyl function of the anionic polysaccharide and the carboxyl function of the hydrophobic acid, the carboxyl functions of the polysaccharide unsubstituted anionic acid in the form of cation carboxylate, preferably alkaline, such as Na ⁺ or K ⁺ .

• Ach being a residue of a hydrophobic acid or hydrophobic O-thioacid • said polysaccharide having carboxyl functional groups being amphiphilic at neutral pH.

In one embodiment, the polysaccharide having carboxyl functional groups partially substituted by hydrophobic acids is chosen from polysaccharides comprising carboxyl functional groups of general formula V:

Polysaccharide + carboxyl

F ¹

Ach

Formula V

in which n represents the molar fraction of the carboxyl functions of the polysaccharide substituted with -F'-Ach and is between 0.01 and 0.7,

F 'and Ach having the definitions given above, and when the carboxyl function of the polysaccharide is not substituted by F'-Ach, then the carboxyl functional group (s) of the polysaccharide are cationic carboxylates, alkali preferably as Na ⁺ or K ⁺ . In one embodiment, the hydrophobic acid is chosen from fatty acids.

In one embodiment, the fatty acids are chosen from the group consisting of acids consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising from 6 to 50 carbons.

In one embodiment, the fatty acids are selected from the group consisting of linear fatty acids.

[000140] In one embodiment, the linear fatty acids are selected from the group consisting of caproic acid, oenanthic acid, caprylic acid, capric acid, nonanoic acid, decanoic acid , undecanoic acid, dodecanoic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, tricosanoic acid, lignoceric acid, heptacosanoic acid, octacosanoic acid and melissic acid. In one embodiment, the fatty acids are selected from the group consisting of unsaturated fatty acids.

In one embodiment, the unsaturated fatty acids are selected from the group consisting of myristoleic acid, palmitoleic acid, oleic acid, elaidic acid, Unoleic acid, alpha-alpha acid and the like. linoleic acid, arachidonic acid, eicosapentaenoid acid, erucic acid and docosahexaenoic acid.

In one embodiment, the fatty acids are selected from the group consisting of bile acids and their derivatives.

In one embodiment, the bile acids and their derivatives are selected from the group consisting of cholic acid, dehydrocholic acid, deoxycholic acid and chenodeoxycholic acid.

In one embodiment, the polysaccharides are polysaccharides comprising carboxyl functional groups of which at least one is substituted with a hydrophobic acid derivative, denoted Ach: embedded image

Said hydrophobic acid (Ach) being grafted or bound to the anionic polysaccharide by a coupling arm R, said coupling arm being linked to the anionic polysaccharide by a function F, said function resulting from the coupling between an amine, alcohol, thioalcohol or carboxyl function; of the precursor of the linker R 'and a carboxyl function of the anionic polysaccharide, and said coupling arm R being linked to the hydrophobic acid by a function G resulting from the coupling between an amine, alcohol, thioalcohol or carboxyl function of the precursor of the coupling arm R 'and a carboxyl function of the hydrophobic acid, the carboxyl functions of the unsubstituted anionic polysaccharide being in the form of a cation carboxylate, preferably alkaline, such as Na ⁺ or K ⁺ .

F being either an amide function, an ester function, a thioester function or an anhydride function,

G is either an ester function, an amide function, an ester function, a thioester function or an anhydride function,

- R being a divalent radical consisting of a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated, optionally comprising one or more heteroatoms, such as O, N or / and S,

- Ach being a residue of an acid, product of the coupling between the carboxyl function of the hydrophobic acid and at least one reactive function carried by the precursor R 'of the divalent radical R,

In one embodiment, F is an amide function, G is an ester function, R 'is an alcoholamine and Ach is a hydrophobic acid residue. [000147] In one embodiment, F is an amide function, G is a thioester function, R 'is a thiolamine and Ach is a hydrophobic acid residue.

In one embodiment, F is an amide function, G is an amide function, R 'is a diamine and Ach is a hydrophobic acid residue.

In one embodiment, F is an amide function, G is an anhydride function, R 'is an amino acid and Ach is a hydrophobic acid residue.

[000150] In one embodiment, F is an ester function, G is an amide function, R 'is an alcoholamine and Ach is a hydrophobic acid residue.

In one embodiment, F is an ester function, G is an ester function, R 'is a dialcohol and Ach is a hydrophobic acid residue. [000152] In one embodiment, F is an ester function, G is a thioester function, R 'is an alcohol thiol and Ach is a hydrophobic acid residue.

In one embodiment, F is an ester function, G is an anhydride function, R 'is an acidic alcohol and Ach is a hydrophobic acid residue.

In one embodiment, F is a thioester function, G is an amide function, R 'is a thiolamine and Ach is a hydrophobic acid residue.

[000155] In one embodiment, F is a thioester function, G is an ester function, R 'is an alcohol thiol and Ach is a hydrophobic acid residue.

[000156] In one embodiment, F is a thioester function, G is a thioester function, R 'is a dithioalcohol and Ach is a hydrophobic acid residue. In one embodiment, F is a thioester function, G is an anhydride function, R 'is an acid thiol and Ach is a hydrophobic acid residue.

In one embodiment, F is an anhydride function, G is an ester function, R 'is an acid alcohol, and Ach is a hydrophobic acid residue.

In one embodiment, F is an anhydride function, G is a thioester function, R 'is an acid thiol and Ach is a hydrophobic acid residue.

In one embodiment, F is an anhydride function, G is an amide function, R 'is an amino acid and Ach is a hydrophobic acid residue.

In one embodiment, F is an anhydride function, G is an anhydride function, R 'is a diacid and Ach is a hydrophobic acid residue. In one embodiment, said polysaccharide having carboxyl functional groups partially substituted by hydrophobic alcohols is chosen from polysaccharides comprising carboxyl functional groups of general formula VI:

Polysaccharide + carboxyl

F

R

BOY WUT

Ach n

Form VI

in which n represents the molar fraction of the carboxyl functions of the polysaccharide substituted with F-R-G-Ach and is between

0.01 and 0.7,

- F, R, G and Ach as defined above, and when the carboxyl function of the polysaccharide is not substituted by FRG-Ach, then the carboxyl functional group (s) of the polysaccharide are carboxylates of cation, alkali of preferably as Na ⁺ or K ⁺ .

In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from amino acids. In one embodiment, the amino acids are selected from alpha amino acids.

[000167] In one embodiment, the hydrophobic alcohol is chosen from fatty alcohols. In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from dialcohols.

In one embodiment, the dialcohols are selected from the group consisting of glycerol, diglycerol and triglycerol. [000170] In one embodiment, the dialcohol is triethanolamine.

In one embodiment, the dialcohols are selected from the group consisting of diethylene glycol and triethylene glycol.

In one embodiment, the dialcoates are chosen from the group consisting of polyethylene glycols without any restriction of mass.

In one embodiment, the alcoholamines are selected from the group consisting of ethanolamine, 2-amino-propanol, isopropanolamine, 3-amino-1,2-propanediol, diethanolamine, diisopropanolamine, tromethamine (Tris) and 2- (2-aminoethoxy) ethanol.

In one embodiment, the alcoholamines are selected from the group consisting of reduced amino acids.

In one embodiment, the reduced amino acids are selected from the group consisting of alaninol, valinol, leucinol, isoleucinol, prolinol and phenylalaninol.

In one embodiment, the alcoholamines are selected from the group consisting of charged amino acids.

[000180] In one embodiment, the charged amino acids are selected from the group consisting of serine and threonine.

In one embodiment, the diacid is selected from the group consisting of succinic acid, glutamic acid, maleic acid, oxalic acid, malonic acid, fumaric acid and the like. glutaconic acid. In one embodiment, the precursor of the group R, R 'is characterized in that it is chosen from the acid alcohols.

In one embodiment, the alcoholic acids are selected from the group consisting of mandelic acid, lactic acid and citric acid.

[000185] In one embodiment, the hydrophobic acid is selected from fatty acids.

[000187] In one embodiment, the fatty acids are chosen from the group consisting of linear fatty acids.

[000188] caproic acid, oenanthic acid, caprylic acid, capric acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, tricosanoic acid, lignoceric acid, heptacosanoic acid, octacosanoic acid and melissic acid.

In one embodiment, the fatty acids are selected from the group consisting of unsaturated fatty acids. [000190] In one embodiment, the unsaturated fatty acids are chosen from the group consisting of myristoleic acid, palmitoleic acid, oleic acid, elaidic acid, linoleic acid, alpha-alpha acid and the like. linoleic acid, arachidonic acid, eicosapentaenoid acid, erucic acid and docosahexaenoic acid. In one embodiment, the fatty acids are chosen from the group consisting of bile acids and their derivatives.

[000192] In one embodiment, the bile acids and their derivatives are selected from the group consisting of cholic acid, dehydrocholic acid, and the like. deoxycholic acid and chenodeoxycholic acid.

[000193] The polysaccharide may have a degree of polymerization m of between 10 and 10,000.

In one embodiment, it has a degree of polymerization m of between 10 and 1000. [000195] In another embodiment, it has a degree of polymerization m of between 10 and 500. In one embodiment, the invention relates to a composition characterized in that the antibody is selected from the group of antibodies and their therapeutically active fragments.

In one embodiment, the antibodies or their fragments are chosen from the group of antibodies or antibody fragments used in oncology with the aim of:

CD 52, VEGF (vascular endothelial growth factor), EGF-R (epidermal growth factor receptor), CD 11a, CCR4 (Chemokine CC receptor 4, chemokine receptor 4), CD 105, CD 123, CD 137, CD 19, CD 22, CD 23, CD 3, CD 30, CD 38, CD 4 , CD 40, CD 55SC-1, CD 56, CD 6, CD 74, CD 80, CS1 (cell-surface glycoprotein 1, cell surface glycoprotein 1), CTLA4 (Cytotoxic T-Lymphocyte Antigen 4, aka: CD152, cytotoxic T lymphocyte antigen 4), DR5 (death receptor 5, cell death receptor 5), Ep-CAM (Epithelial cell Adhesion Molecule, epithelial cell adhesion molecule), folate receptor alpha the alpha folate receptor, ganglioside GD2, ganglioside GD3, GPIMMB, glycoprotein NMB, HGF / SF (hepatocyte growth factor / scatter factor, growth factor or disp Hepatocyte ersion), IGF-1 (insulin-like growth factor, insulin-like growth factor), IGF1-Receptor (Insulin-like growth factor-1 Receptor, growth factor receptor similar to insulin), 11 L 13 (interleukin-13), HL 6 (interleukin-6), IL-6R (interleukin-6 receptor, interleukin-6 receptor), fungal immunodominant antigen heat shock protein 90 (hsp90) , integrin alpha 5 beta 3, MHC (major histocompatibility complex) class II or major histocomaptibility complex type II, MN antigen (also called G250-antigen, MN or G250 antigen), MUC1, PD -I (programmed death 1, programmed death protein 1), the PIGF (Placenta! Growth factor, placental growth factor), PDGFRα (platelet derived growth factor receptor alpha, alpha receptor for platelet-derived growth factor), the prostate specifies antigen membrane, (PSMA, prostate membrane specific antigen), PTHrP (parathyroid hormone related protein, protein similar to parathyroid hormone), CD200 Receptor, Receptor activator of nuclear factor kappa B ligand (RANKL, kappa B nuclear factor activator receptor ligand), sphingosine-1-phosphate ( SlP), TGF beta (transforming growth factor beta), the TRAIL (tumor necrosis factor (TNF) -related apoptosis-inducing ligand) receptor 1, (receptor 1 of TNF-inducing apoptosis-inducing ligand), tumor necrosis factor receptor 2 (tumor necrosis factor receptor 2), vascular endothelial growth factor receptor 2 (VEGFR-2, vascular endothelial growth factor receptor 2), CD 33, CD 20 or CA 125 (antigen 125 cancer, 125 cancer antigen).

[000198] In one embodiment, the antibodies are chosen from the group of antibodies comprising alemtuzumab, bevacizumab, cetuximab, efalizumab, gemtuzumab, britumomab, ovarex mab, panitumumab, rituximab, tositumomab or trastuzumab.

[000199] In one embodiment, the antibodies are chosen from the group of antibodies or antibody fragments used in dermatology that target:

- TIMF alpha (tumor necrosis factor alpha, tumor necrosis factor alpha), IL 12, IL 15, IL 8, interferon alpha, CD 3.

In one embodiment, the antibodies are chosen from the group of antibodies comprising adalimumab, IΑBT874, etanercept, IΑMG714, HuMax-IL8, MEDI545, otelixizumab or infliximab.

In one embodiment, the antibodies are chosen from the group of antibodies or antibody fragments used in respiratory and pulmonary diseases that target:

- IL 4, the I ¹ receptor IL 5, IL 1 IL 1, IL 13, tumor necrosis factor receptor 1 (TNFRl, receptor 1 tumor necrosis factor) 25 CD (cluster of differentiation 25, differentiation cluster 25), CTGF (Connective Tissue Growth Factor, TNF alpha, tumor necrosis factor alpha, tumor necrosis factor alpha), GM-CSF (granulocyte monocyte colony stimulating factor, granulocyte colony stimulating factor), CD 23, RSV, Respiratory Syncitial Virus (IL-5), IL-5, Staphylococcus aureus dumping factor A (Staphylococcus aureus aggregation factor A) tissue factor (tissue factor), IgE, immunoglobulin E or RSV (Respiratory Syncitial Virus-Respiratory Syncitial Virus). [000202] In one embodiment, the antibodies are selected from the group of antibodies comprising IΑMG317, Anti-IL13, BIW-8405, canakinumab, CAT354, CNTO148, Daclizumab, FG-3019, GC-1008, golimumab, KB002, lumiliximab, MEDI557, mepolizumab, QAX576, tefibazumab, TNX-832, omalizumab or palivizumab

[000203] The antibodies used in autoimmune and inflammatory diseases, chosen from antibodies or antibody fragments targeting: TNF alpha (tumor necrosis factor alpha, alpha tumor necrosis factor), CD25 ( cluster of differentiation 25, differentiation cluster 25), CD, LFA-I (lymphocyte function-associated antigen, antigen associated with lymphocyte function), CD 3, IgE (immunoglobulin E), IL 6, B7RP B7 (B7 related protein, protein similar to B7 protein), Blys (B lymphocyte stmulator, B cell stimulator), CCR4 (Chemokine CC receptor 4, CC chemokine receptor 4), CD IIa, CD 20 (cluster of differentiation 20, differentiation cluster 20), CD 22 (cluster of differentiation 22, differentiation cluster 22), CD 23, CD 4, CD 40, CD 44, CD 95, CXCL10, eotaxin 1, GM-CSF (granulocyte monocyte colony stimulating factor, colony stimulating factor granulocytes), IL 1 (interleukin 1), IL 12, IL 13, IL 15, IL 18, IL 5, IL 8, IL 23, Integrin alpha 4 beta 7, alpha 4 beta 1 or alpha 4 beta 7 interferon, interferon alpha, interferon gamma, interleukin-17 receptor, receptor activator of nuclear factor kappa B ligand (RANKL, receptor ligand kappa nuclear factor activator B), VAP-I (Vascular Adhesion Protein-1) inflammation receptor (vascular adhesion protein-1 receptor inflammation) or VAP-I (vascular adhesion protein-1, protein vascular adhesion 1).

[000204] In one embodiment, the antibodies are chosen from the group of antibodies comprising adalimumab, basiliximab, daclizumab, efalizumab, muromonab-CD3, omalizumab or tocilizumab. [000205] In one embodiment, the antibodies are chosen from the group of antibodies or antibody fragments used in cardiovascular and circulatory diseases whose target is:

glycoprotein Ilb / IIIa receptor of human platelets, human platelet glycoprotein Ilb / IIIa, oxidized low density lipoprotein

(oxLDL, oxidized low-density lipoprotein), digoxin or factor VIII

In one embodiment, the antibodies are selected from the group of antibodies comprising abciximab, 7E3, BI-204, Digibind or TB402.

In one embodiment, the antibodies are chosen from the group of antibodies or antibody fragments used in diseases of the central nervous system that are targeted at: CD 52, alpha 4 beta 1 or alpha 4 integrins beta I ₁ beta amyloid peptide, IL 12, IL 23, CD 25 (cluster of differentiation 25- differentiation cluster 25), myelin associated glycoprotein (MAG, myelin-associated glycoprotein, CD 20, or NGF (neural growth factor).

In one embodiment, the antibodies are selected from the group of antibodies comprising alemtuzumab, natalizumab, IΑBT874, Bapineuzumab, CNTO 1275, Daclizumab, GSK249320, rituximab, RN624.

In one embodiment, the antibodies are selected from the group of antibodies or antibody fragments used in gastrointestinal diseases with the target of:

TNF alpha (tumor necrosis factor alpha, tumor necrosis factor alpha), CD25 (cluster of differentiation 25, cluster of differentiation 25), toxin A of Clostridium difficile, CXCL10, IL5 or integrins alpha 4 beta 1 or alpha 4 beta 7.

[000210] In one embodiment, the antibodies are selected from the group of antibodies comprising infliximab, adalimumab, basiliximab, CNTO148, golimumab, MDX066, MDX1100, mepolizumab, MLN02 or Reslizumab. [000211] The antibodies used in infectious diseases, chosen from antibodies or antibody fragments targeted at:

Hepatitis C envelope envelope protein 2, PS (Phosphatidyl Serine, phosphatidyl serine), lipoteichoic acid, penicillin-binding protein (PBP protein binding to penicillin), CD4, CTLA4 ( Cytotoxic T-Lymphocyte Antigen 4, aka: CD152, cytotoxic T lymphocyte antigen 4)), PD-I (programmed death 1, programmed death protein 1), West IMi Virus, western NU virus), Fungal antigen heat shock protein 90, CCR5 (chemokine CC receptor 5, CC chemokine receptor 5), rabies virus, Bacillus anthracis protection antigen, Staphylococcus aureus dumping factor A (Staphylococcus aureus aggregation factor A), Stx2 or TNF alpha, (tumor necrosis factor alpha, tumor necrosis factor alpha). In one embodiment, the antibodies are chosen from the group of antibodies comprising Bavituximab PEREGRINE, BSYXA110, cloxacillin, ibalizumab, MDX010, MDX1106, MGAWN1, Mycograb, Prol40, Rabies Antibody, raxibacumab, tefibazumab or TMA15.

In one embodiment, the antibodies are chosen from the group of antibodies or antibody fragments used in metabolic diseases and in endocrinology that target:

IL-1 (interleukin-1), GCGR (glucagon receptor, glucagon receptor), PTHrP (parathyroid hormone related protein, parathyroid hormone-like protein) or CD-3.

In one embodiment, the antibodies are chosen from the group of antibodies comprising TIOR-T3, IΑMG108, IΑMG477, CAL, canakinumab, otelixizumab, Teplizumab or XOMA052.

[000215] In one embodiment, the antibodies are chosen from the group of antibodies or antibody fragments used in female metabolic diseases that target:

the receptor activator of nuclear factor kappa B ligand (RANKL, ligand of the activating receptor of the nuclear factor kappa B)

In one embodiment, the antibodies are selected from the group of antibodies comprising Denosumab. [000217] In one embodiment, the antibody is cetuximab. [000218] In one embodiment, the antibody is bevacizumab.

The invention also relates to a method for optimizing the stabilization of a formulation of a monoclonal antibody comprising the following steps:

• a monoclonal antibody is available

The library of amphiphilic polymers comprising the above-defined polysaccharides is available; the thermal stabilization of said antibody is measured;

The amphiphilic polysaccharide (s) capable of providing the best stabilization at the concentrations of the pharmaceutical formulations are determined.

Said antibody is formulated in the presence of said at least one amphiphilic polysaccharide (s).

In one embodiment, the measurement of the thermal stabilization is performed by incubation of the antibody or complex at 56 ° C for 1 to 5 days. When the antibody alone or complexed is destabilized, it aggregates. This aggregation is monitored by measuring light scattering at 450 nm.

[000221] The invention also relates to a pharmaceutical formulation comprising a composition according to the invention in which the polysaccharide / antibody molar ratio of between 0.2 and 20, preferably between 0.5 and 10.

[000222] The concentration of antibodies in the formulations is preferably in the range of from 1 mg / ml to about 250 mg / ml. This concentration is determined by the method of formulation, for example for an intravenous formulation the concentration will be between 1 and 50 mg / ml, for a subcutaneous or intramuscular formulation the concentration will be between 50 mg / ml and about 200 mg / ml. [000223] The formulations are preferably aqueous formulations. The formulations according to the invention may further comprise surfactants such as, for example, polysorbate in concentrations of between 0.0001 and 1.0%.

The formulation may contain a nonionic salt or sepecium to maintain or restore isotonicity, for example sodium chloride, glycerol or trehalose.

Example 1 Synthesis of Dodecylamine Modified Sodium Dextranemethylcarboxylate, Polymer 1

[000226] 8 g (148 mmol of hydroxyl functional groups) of dextran with a weight average molar mass of approximately 40 kg / mol (Fluka) are solubilized in water at 42 g / l. To this solution are added 15 ml of 10 N NaOH (148 mmol NaOH). The mixture is brought to 35 ° C and then 23 g (198 mmol) of sodium chloroacetate are added. The temperature of the reaction medium is brought to 60 ^° C. for 100 minutes. The reaction medium is diluted with 200 ml of water, neutralized with acetic acid and purified by ultrafiltration on PES membrane 5 kD against 6 volumes of water. The final solution is assayed by dry extract to determine the polymer concentration; then assayed by acid / base assay in water / acetone 50/50 (V / V) to determine the degree of substitution of methylcarboxylates. According to the dry extract: [polymer] = 31.5 mg / g [000228] According to the acid / base assay: The degree of substitution of the hydroxyl functions by methylcarboxylate functions is 1.04 per saccharide unit.

The sodium dextranmethylcarboxylate solution is passed through a Purolite resin (anionic) to obtain the acid dextran-methylcarboxylic acid which is then freeze-dried for 18 hours.

7.5 g of dextran-methyl-carboxylic acid (34 mmol of acid methylcarboxylic functions) are solubilized in DMF at 45 g / l and then cooled to 0 ^° C. 0.65 g of dodecylamine (3.5 mmol) and 3, 69 g of triethylamine are suspended in DMF at 100 g / l. Once the polymer solution at 0 ^° C., 3.69 g (36 mmol) of N-methylmorpholine and 4.98 g (36 mmol) of isobutyl chloroformate are then added. After 10 min of reaction, the solution of dodecylamine and triethylamine is added. The middle is then maintained at 100 ^° C. for 3 hours and then heated at 20 ^° C. Once at 20 ^° C., 10 ml of water are added. The medium is poured into 820 ml of a 50/50 water / ethanol solution with vigorous stirring. The solution is ultrafiltered on a 5 kD PES membrane against 10 volumes of 0.9% NaCl solution and then 5 volumes of water. The concentration of the polymer solution is determined by dry extract. A solution fraction is lyophilized and analyzed by 1H NMR in D2O to determine the rate of acid functions converted to dodecylamide. According to the dry extract: [Polymer 1] = 25.9 mg / g [000232] According to the 1 H NMR: the mole fraction of the acids modified with dodecylamine per saccharide unit is 0.10.

Example 2 Synthesis of Cholesterol Leucinate-Modified Sodium Dextranemethylcarboxylate, Polymer 2

[000233] The cholesterol leucinate, paratoluenesulfonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818).

The sodium dextranmethylcarboxylate solution described in Example 1 is passed over a Purolite resin (anionic) to obtain the acid dextranmethylcarboxylic acid which is then lyophilized for 18 hours.

[000235] 8 g of dextran-methyl-carboxylic acid (37 mmol methylcarboxylic acid function) are solubilized in DMF at 45 g / l and then cooled to 0 ^° C. 0.73 g of cholesterol leucinate, para-toluenesulphonic acid salt (1 mmol) is suspended in DMF at 100 g / L. 0.11 g of triethylamine (1 mmol) is then added to this suspension. Once the polymer solution at 0 ^° C., 0.109 g (1 mmol) of NMM and 0.117 g (1 mmol) of EtOCOCI are then added. After 10 minutes of reaction, the suspension of cholesterol leucinate is added. The medium is then maintained at 4 ° C. for 15 minutes. The medium is then heated to 30 ^° C. Once at 30 ^° C., the medium is then poured into a solution of 3.76 g of NMM (37 mmol) at 5 g / l with vigorous stirring. The solution is ultrafiltered on a 10 kD PES membrane against 10 volumes of 0.9% NaCl solution and then 5 volumes of water. The concentration of the polymer solution is determined by dry extract. A solution fraction is lyophilized and analyzed by 1H NMR in D2O to determine the rate of acid functions converted to cholesterol leucinate amide. [000236] According to the dry extract: [Polymer 2] = 12.9 mg / g

According to the 1 H NMR: the molar fraction of the acids modified with cholesterol leucinate per saccharide unit is 0.03.

Example 3 Synthesis of cholesteryl leucinate-modified sodium dextransuccinate, Polymer 3

The cholesterol leucinate, para-toluenesulfonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818). Sodium dextransuccinate is obtained from dextran 40 according to the method described in the article by Sanchez-Chaves et al. (Sanchez-Chaves, Manuel et al., Polymer 1998, 39 (13), 2751-2757.) The rate of acid functions per glycosidic unit (i) is 1.46 according to 1H NMR in D2O / NaOD. The sodium dextransuccinate solution is passed through a Purolite resin (anionic) to obtain the dextransuccinic acid which is then lyophilized for 18 hours.

[000241] 7.1 g of dextransuccinic acid (23 mmol) are solubilized in DMF at 44 g / l. The solution is cooled to 0 ^° C. 0.77 g of cholesterol leucinate, salt of para-toluenesulphonic acid (1 mmol) is suspended in DMF at 100 g / l. 0.12 g of triethylamine (TEA) (1 mmol) is then added to this suspension. Once the polymer solution at 0 ^° C., 0.114 g (1 mmol) of NMM and 0.124 g (1 mmol) of EtOCOCI are then added. After 10 minutes of reaction, the suspension of cholesterol leucinate is added. The medium is then maintained at 4 ° C. for 15 minutes. The medium is then heated to 30 ^° C. Once at 30 ^° C., the medium is then poured into a solution of 3.39 g of NMM (33 mmol) at 5 g / l with vigorous stirring. The solution is ultrafiltered on a 10 kD PES membrane against 10 volumes of 0.9% NaCl solution and then 5 volumes of water. The concentration of the polymer solution is determined by dry extract. A fraction of solution is lyophilized and analyzed by 1H NMR in D2O to determine the level of acid functions converted to cholesterol leucinate amide.

According to the dry extract: [Polymer 3] = 17.5 mg / g [000243] According to the 1 H NMR: the molar fraction of the acids modified with cholesterol leucinate per saccharide unit is 0, 05. Example 4 Synthesis of Octanol Glycinate Modified Sodium Dextranemethylcarboxylate, Polymer 4

[000244] Octanol glycinate, para-toluenesulfonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818). By a method similar to that described in Example 2, a sodium dextranethyl carboxylate modified with octanol glycinate is obtained.

According to the dry extract: [Polymer 4] = 34.1 mg / g [000247] According to the 1 H NMR: the molar fraction of acids modified with octanol glycinate per saccharide unit is 0. 1.

EXAMPLE 5 Synthesis of Sodium Dextran Methylcarboxylate Modified by Isohexanol Leucinate, Polymer 5

The isohexanol leucinate, para-toluenesulfonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818).

By a method similar to that described in Example 2, a sodium dextranmethylcarboxylate modified with isohexanol leucinate is obtained.

According to the dry extract: [Polymer 5] = 16 mg / g [000251] According to the 1 H NMR: the molar fraction of the acids modified with isohexanol leucinate per saccharide unit is 0.17 .

EXAMPLE 6 Synthesis of Dodecanol Phenylalaninate Modified Sodium Dextranemethylcarboxylate, Polymer 6 [000252] Dodecanol phenylalaninate, paratoluene sulphonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818) .

By a method similar to that described in Example 2, a sodium dextranmethylcarboxylate modified with dodecanol phenylalaninate is obtained.

[000254] According to the dry extract: [Polymer 6] = 20 mg / g

According to the 1 H NMR: the molar fraction of the acids modified with dodecanol phenylalaninate per saccharide unit is 0.1. Example 7 Synthesis of Benzyl Alcohol Phenylalaninate Modified Sodium Dextranemethylcarboxylate, Polymer 7

By a method similar to that described in Example 2, a benzyl alcohol phenylalaninate modified sodium dextranemethylcarboxylate is obtained by using benzyl alcohol phenylalaninate, hydrochloric acid salt (Bachem).

According to the dry extract: [Polymer 7] = 47.7 mg / g [000258] According to 1H NMR; the molar fraction of benzyl alcohol phenylalaninate modified acids per saccharide unit is 0.41.

Example 8 Synthesis of sodium dextranmethylcarboxylate modified with dodecanol glycinate, Polymer 8

[000259] Dodecanol glycinate, paratoluene sulphonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818). By a method similar to that described in Example 2, a sodium dextranmethylcarboxylate modified with dodecanol glycinate is obtained.

According to the dry extract: [Polymer 8] = 25.3 mg / g [000262] According to 1 H NMR: the molar fraction of acids modified with dodecanol glycinate per saccharide unit is 0, 1.

Example 9 Synthesis of Deoxtranethyl Methylcarboxylate Modified by Decanol Glycinate, Polymer 9

[000263] Decanol glycinate, paratoluene sulphonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818).

By a method similar to that described in Example 2, a sodium dextranmethylcarboxylate modified with the decanol glycinate is obtained.

According to the dry extract: [Polymer 9] = 23.1 mg / g [000266] According to the RMIM III: the mole fraction of acids modified with dodecanol glycinate per saccharide unit is 0, 1.

EXAMPLE 10 Synthesis of Octanol Modified Sodium Dextranemethylcarboxylate, Polymer IO [000267] 1-Octyl p-toluenesulfonate is obtained according to the process described in the publication (Morita, J.I. et al., Green Chem. 2005, 7, 711). The sodium dextranemethylcarboxylate is synthesized according to the process described in Example 1 using a dextran with a weight average molecular weight of approximately 10 kg / mol (Pharmacosmos). The sodium dextranmethylcarboxylate solution is passed through a Purolite resin (anionic) to obtain an aqueous solution of acid dextranemethylcarboxylic acid whose pH is raised to 7.1 by addition of an aqueous solution (40%) of sodium hydroxide. tetrabutylammonium (Sigma) then the solution is then lyophilized for 18 hours. [000270] 20 g of tetrabutylammonium dextranemethylcarboxylate (45 mmol methylcarboxylate functions) are solubilized in DMF at 120 g / l and then heated at 40 ^° C. A solution of 2.37 g of 1-octyl p-toluenesulphonate (8.3 mmol) in 12 ml of DMF is then added to the polymer solution. The medium is then maintained at 40 ^° C. for 5 hours. The solution is ultrafiltered on a 10 kD PES membrane against 15 volumes of 0.9% NaCl solution and then 5 volumes of water. The concentration of the polymer solution is determined by dry extract. A solution fraction is lyophilized and analyzed by 1H-NMR in D2O to determine the rate of acid functions converted to 1-octanol ester. According to the dry extract: [Polymer 10] = 20.2 mg / g [000272] According to 1 H-NMR: the molar fraction of acids modified with 1-octanol per saccharide unit is 0, 17.

Example 11 Synthesis of Dodecanol Modified Sodium Dextranemethylcarboxylate, Polymer 11 [000273] 1-Dodecenyl p-toluenesulfonate is obtained according to the process described in the publication (Morita, J.-I. et al., Green Chem., 2005 , 7, 711). By a method similar to that described in Example 10, using a dextran with a weight average molecular weight of approximately 10 kg / mol (Pharmacosmos), a sodium dextranmethylcarboxylate modified with dodecanol is obtained.

[000275] According to the dry extract: [Polymer 11] = 18.7 mg / g

According to the 1 H NMR: the mole fraction of the acids modified with dodecanol per saccharide unit is 0.095. Example 12 Synthesis of Sodium Dextran Methylcarboxylate Modified with Phenylalaninol Caprylate Ester, Polymer 13

[000277] The phenylalaninol caprylate ester, para-toluenesulfonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818).

By a method similar to that described in Example 2, a sodium dextranmethylcarboxylate modified with phenylalaninol caprylate ester is obtained.

According to the dry extract: [Polymer 13] = 25 mg / g [000280] According to the 1 H NMR: the molar fraction of the acids modified with the phenylalaninol caprylate ester per saccharide unit is 0.045.

Example 13 Synthesis of Ethanolamine Caprylate Modified Sodium Dextranemethylcarboxylate, Polymer 14 [000281] Ethanolamine caprylate ester, para-toluenesulfonic acid salt is obtained according to the method described in the patent (Kenji, M et al. , US4826818). By a method similar to that described in Example 2, a sodium dextranethylcarboxylate modified with ethanolamine caprylate ester is obtained. [000283] According to the dry extract: [Polymer 14] = 29.1 mg / g

According to the 1 H NMR: the molar fraction of the acids modified with the ethanolamine caprylate ester per saccharide unit is 0.15.

Example 14 Synthesis of Ethanolamine Laurate Ester-Modified Sodium Dextranemethylcarboxylate, Polymer 15

[000285] The ethanolamine laurate ester, paratoluenesulfonic acid salt is obtained according to the process described in the patent (Kenji, M et al., US4826818). By a method similar to that described in Example 2, a sodium dextranethylcarboxylate modified with ethanolamine laurate ester is obtained.

[000287] According to the dry extract: [Polymer 15] = 21.2 mg / g

According to the 1 H NMR: the molar fraction of the acids modified with the laurate ester of ethanolamine per saccharide unit is 0.09. Example 15: Counterexample 1, Synthesis of Dextranemethylcarboxylate Unmodified by a Hydrophobic Group, Polymer 16

The sodium dextranemethylcarboxylate is obtained as described in the first part of Example 1. The mole fraction of the acids modified with a hydrophobic group is zero.

EXAMPLE 16 Thermal Stabilization of the Antibodies by Complexation with the Polymers Description of the stability test

This test makes it possible to measure the thermal stabilization of monoclonal antibodies by interaction with polymers. The thermal stability is by incubation of the antibody or complex at 56 ° C for 1 to 5 days. When the antibody alone or complexed is destabilized, it aggregates. This aggregation is monitored by measuring light scattering at 450 nm.

Determination of the concentration of antibody study

[000291] Despite their similarity, the monoclonal antibodies have different solubilities or stabilities at the formulation concentrations.To use this test, it is first necessary to determine an antibody concentration that makes it possible to measure a sufficient destabilization signal. μl of monoclonal antibody at concentrations of 1, 2, 4, 6, 10 mg / ml, for example, is incubated at 56 ° C. for 48 hours, the absorbance at 450 nm is measured at t0 and at t48h. The study is determined as the minimum concentration at which the difference in absorbance between t48h and t0 is at least 0.5 for an optical path of 1 cm.

Study of stabilization due to polymers

[000292] 100 μl of antibody at 2 times the study concentration are mixed with 100 μl of polymer at the same molar concentration in order to obtain an antibody solution at the study concentration in the presence of a molar ratio polymer. 1/1. The formulation is incubated at 56 ^° C. for 5 days and the absorbance at 450 nm is measured at t0, t24h, t48h and t96h then every 24 hours. A polymer is judged positively (+) if it leads to a lower absorbance than that obtained with the antibody alone at the different analysis times. A polymer is considered very positively (++) if it leads to a absorbance much lower than that obtained with the antibody alone at different analysis times. In both cases, this indicates a lower aggregation of the monoclonal antibody and therefore a thermal stabilization of the monoclonal antibody by the polymer. The polymer is judged negatively (-), if it leads to an absorbance substantially identical to that obtained with the antibody alone at the different analysis times.

Results obtained:

Cetuximab (ERBITUX) at 1.3 mg / ml

Bevacizumab (AVASTIN) at 6 mg / ml

Example 17 Study of the Effect of the Length of the Carbon Chain of the Graft on Stabilization

[000293] The polymers 4, 9 and 8 are distinguished by the length of their fatty chain ranging from a C8 to a C12. Their stabilizing effect described in Example 17 is recalled in the following table.

The results obtained clearly show that increasing the length of the fatty chain induces a better stabilization.

Example 18 Study of Stabilization Due to Polymers as a Function of Ionic Strength

6.4 ml of avastin at 25 mg / ml, 50 mM Phosphate pH 6.2 is mixed with 0.165 ml of 4 M NaCl and 1.435 ml of 50 mM phosphate to obtain Avastin 20 mg / ml in 50 mM. Phosphate, 83 mM NaCl. To 2.5 ml of this Avastin solution is added 2.5 ml of Polymer 8 at 11 mg / ml in 50 mM Phosphate pH 6.2, 83 mM NaCl, which makes it possible to obtain a solution of polymer / Avastin complex. 2: 1 molar ratio containing 10 mg / ml of Avastin. An identical solution is prepared without polymer.

[000296] 2 ml of each solution are stored for the study of high ionic strength stabilization and 3 ml are diafiltered to obtain a low ionic strength sample: 3 ml of Avastin / Polymer complex or Avastin solution alone are diluted 4 times by adding 9 ml of H2O and then centrifuged in an amicon with a 10 kD membrane until a volume of 3 ml. This step is repeated twice with 5 mM Phosphate pH 6.2 buffer.

The four formulations are incubated at 56 ° C. for 4 days and the absorbance at 450 nm is measured at TO, T60h and T80h. A decrease in the increase in absorbance over time compared to that of the antibody alone indicates a lower aggregation and thus a thermal stabilization of the antibody.

Under these conditions, the formulations containing the complex are more stable than those containing the antibody alone. In addition, the stability is increased when the ionic strength decreases.

Example 19 Stabilization of a monoclonal antibody with respect to mechanical stress

[000299] The monoclonal antibody Avastin is diluted to 2 mg / ml from a stock in solution at 25 mg / ml and 50 mM phosphate, pH 6.2 (a first dilution is carried out to 1 / 5th of water purified and a subsequent 2 / 5ths with 10 mM phosphate buffer). The final phosphate concentration is 10 mM. A polymer solution is prepared from lyophilisate in a 10 mM phosphate buffer, pH 6.2, such that the volume-to-volume mixture with the preceding solution makes it possible to obtain the monoclonal antibody at 1 mg / ml, 10 mM. of phosphate and a polymer / antibody molar ratio of 3. The formulations are then filtered on a 0.22 μm porosity filter and distributed in a transparent HPLC bottle of 2 ml.

The samples are then exposed to mechanical stress using a magnetic bar having a glass surface, at a speed of 130 rpm. Samples are taken at various times and analyzed by dynamic light scattering to determine the aggregation state of the antibody. [000301] A sample is designated "+" if the aggregation is moderately inhibited by the polymer present. A sample is designated by

"++", if the aggregation is more strongly inhibited. A sample is designated "+++" if the aggregation is very strongly inhibited by the polymer present.

The results are given in the table below:

The effect of the polymer not modified by a hydrophobe, Polymer 16, on the aggregation of the antibody induced by the mechanical stress is low. In contrast, hydrophobe-modified polymers have a greater effect on aggregation inhibition up to stabilization for Polymer 8.

Claims

A stable pharmaceutical composition comprising at least one monoclonal antibody and at least one amphiphilic polysaccharide.

2. Composition according to claim 1, characterized in that the amphiphilic polysaccharide is selected from the group of amphiphilic polysaccharides having carboxyl functional groups partially substituted by at least one hydrophobic substituent.

3. Composition according to any one of claims 1 to 2, characterized in that the amphiphilic polysaccharide is selected from polysaccharides having carboxyl functional groups of which at least one is substituted by a hydrophobic radical, noted Hy:

Said hydrophobic radical (Hy) being grafted or bonded to the anionic polysaccharide;

F being either an amide, ester, thioester or anhydride function,

F 'being either an amide, ester, thioester or anhydride function, G being either an amide, ester, thioester, thionoester carbamate, carbonate or anhydride function,

Where Hy is a radical resulting either from the coupling between a reactive functional group of a hydrophobic compound and a carboxyl function of the anionic polysaccharide, or from the coupling between a reactive functional group of a hydrophobic compound and a reactive function of the precursor of the linking arm R ' . consisting of a chain comprising between 4 and 50 carbons, optionally branched and / or unsaturated, optionally comprising one or more heteroatoms, such as O, N or / and S, optionally comprising one or more saturated, unsaturated or aromatic rings or heterocycles,

R being a divalent radical consisting of a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated, optionally comprising one or more heteroatoms, such as O, N or / and S, optionally comprising one or more rings or heterocycles; saturated, unsaturated or aromatic and resulting from the reaction of a precursor R 'having at least two reactive functions, identical or different, selected from the group consisting of alcohol, acid, amine, thiol and thioacid functions. Said polysaccharide comprising carboxyl functional groups being amphiphilic at neutral pH.

4. Composition according to any one of claims 1 to 2, characterized in that the amphiphilic polysaccharides are chosen from polysaccharides comprising carboxyl functional groups, at least one of which is substituted by a hydrophobic alcohol derivative, denoted by Ah:

Said hydrophobic alcohol (Ah) being grafted or bound to the anionic polysaccharide by a coupling arm R, said coupling arm being linked to the anionic polysaccharide by a function F, said function resulting from the coupling between an amine, alcohol, thioalcohol or carboxyl function; of the precursor of the linker R 'and a carboxyl function of the anionic polysaccharide, and said coupling arm R being linked to the hydrophobic alcohol by a function G resulting from the coupling between a carboxyl, amine, thioacid or alcohol function of the precursor of the arm R 'and an alcohol function of the hydrophobic alcohol, the carboxyl functions of the nonionic polysaccharide substituted in the form of a cation carboxylate, preferably alkaline, such as Na ⁺ or K ⁺ .

F being either an amide function, an ester function or a thioester function, or an anhydride function - G being either an ester function or a thioester function, or a carbonate function or a carbamate function,

- Ah being a residue of a hydrophobic alcohol or thioalcohol, produced coupling between the hydroxyl function of the hydrophobic alcohol and at least one reactive function carried by the precursor of the divalent radical R, • said polysaccharide comprising carboxyl functional groups being amphiphilic at neutral pH.

5. Composition according to any one of claims 1 to 2, characterized in that the amphiphilic polysaccharides are chosen from polysaccharides comprising carboxyl functional groups, at least one of which is substituted by a hydrophobic alcohol derivative, denoted by Ah:

Said hydrophobic alcohol (Ah) being grafted or bound to the anionic polysaccharide by a function F ', said function F resulting from the coupling between the carboxylate function of the anionic polysaccharide and the hydroxyl function of the hydrophobic alcohol, the carboxyl functions of the unsubstituted anionic polysaccharide being in the form of a cation carboxylate, preferably alkaline, such as Na + or KK

F 'being an ester or thioester function,

• Ah being a residue of a hydrophobic alcohol, or hydrophobic thioalcohol,

6. Composition according to any one of claims 1 to 2, characterized in that the amphiphilic polysaccharide is selected from the group of polysaccharides having carboxyl functional groups of which at least one is substituted by a hydrophobic amine derivative, denoted Amh: said hydrophobic amine being grafted or bound to the anionic polysaccharide by an amide function F 'said amide function F' resulting from the coupling between the amine function of the hydrophobic amine and a carboxyl function of the anionic polysaccharide, the carboxyl functions of the unsubstituted anionic polysaccharide being in the form of a cation carboxylate, preferably alkaline, such as Na + or K +.

Amh being a residue of a hydrophobic amine, product of the coupling between the amine function of the hydrophobic amine and a carboxyl functional function of the anionic polysaccharide.

7. Composition according to any one of claims 1 to 2, characterized in that the amphiphilic polysaccharide is selected from the group of polysaccharides having carboxyl functional groups of which at least one is substituted by a hydrophobic acid derivative, denoted Ach:

Said hydrophobic acid (Ach) being grafted or bound to the anionic polysaccharide by an anhydride function F ', said function F resulting from the coupling between the carboxyl function of the anionic polysaccharide and the carboxyl function of the hydrophobic acid, the carboxyl functions of the nonionic polysaccharide substituted in the form of a cation carboxylate, preferably alkaline, such as Na + or K +. Ach being a residue of a hydrophobic acid or hydrophobic O-thioacid

8. Composition according to any one of claims 1 to 2, characterized in that the amphiphilic polysaccharide is selected from the group of polysaccharides having carboxyl functional groups of which at least one is substituted by a hydrophobic acid derivative, denoted Ach:

Said hydrophobic acid (Ach) being grafted or bound to the anionic polysaccharide by a coupling arm R, said coupling arm being bonded to the anionic polysaccharide by a function F, said function F resulting from the coupling between an amine, alcohol, thioalcohol or carboxyl function of the precursor of the linker arm R 'and a carboxyl function of the anionic polysaccharide, and said coupling arm R being linked to the hydrophobic acid by a function G resulting from the coupling between an amine, alcohol, thioalcohol or carboxyl function of the precursor of the coupling arm R 'and a carboxyl function of the hydrophobic acid, the carboxyl functions of the unsubstituted anionic polysaccharide being in the form of cation carboxylate, alkali preferably as Na ⁺ or K ⁺ . F being either an amide function, an ester function, a thioester function or an anhydride function,

G is either an ester function, an amide function, an ester function, a thioester function or an anhydride function, R being a divalent radical consisting of a chain comprising between 1 and 18 carbons, optionally branched and / or or unsaturated, optionally comprising one or more heteroatoms, such as O, N and / or S,

9. Composition according to any one of the preceding claims, characterized in that the polysaccharides comprising carboxyl functional groups are polysaccharides naturally carrying carboxyl functional groups and are chosen from the group consisting of alginate, hyaluronan and galacturonan.

10. Composition according to any one of the preceding claims, characterized in that the polysaccharides comprising carboxyl functional groups are synthetic polysaccharides obtained from polysaccharides naturally having carboxyl functional groups or from neutral polysaccharides on which less than 15 carboxyl functional groups per 100 saccharide units have been grafted of general formula IL

the natural polysaccharides being chosen from the group of polysaccharides consisting mainly of glycoside bonds of (1,6) and / or (1,4) and / or (1,3) and / or (1,2) type,

L being a bond resulting from the coupling between the linker Q and an OH function of the polysaccharide and being either an ester, thioester, carbonate, carbamate or ether function,

Q being a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, N and / or S, and comprising at least one carboxyl functional group, - CO ₂ H

11. Composition according to any one of the preceding claims, characterized in that the polysaccharide consists predominantly of glycoside bonds of (1,6) type and is dextran.

12. Composition according to any one of claims 1 to 10, characterized in that the polysaccharide consists predominantly of glycoside bonds of (1,4) type and is selected from the group consisting of pullulan, alginate, hyaluronan, xylan, galacturonan or water-soluble cellulose.

13. Composition according to any one of claims 1 to 10, characterized in that the polysaccharide consists predominantly of glycoside bonds of (1,3) type, and is a curdlane.

14. Composition according to any one of claims 1 to 10, characterized in that the polysaccharide consists predominantly of glycoside bonds of type (1,2), and is an inulin.

15. Composition according to any one of claims 1 to 10, characterized in that the polysaccharide consists predominantly of glycoside bonds of (1,4) and (1,3) type, and is a glucan.

16. Composition according to any one of claims 1 to 10, characterized in that the polysaccharide consists mainly of glycoside bonds of (1,4), and (1,3) and (1,2) type, and the mannan.

17. Composition according to one of the preceding claims characterized in that the antibody is selected from the group of antibodies or antibody fragments used in oncology targeting:

CD 52, VEGF (vascular endothelial growth factor), EGF-R (epidermal growth factor receptor), CD 11a, CCR4 (Chemokine CC receptor 4, receiver

4 chemokines CC), CD 105, CD 123, CD 137, CD 19, CD 22, CD 23, CD 3, CD 30, CD 38, CD 4, CD 40, CD 55SC-1, CD 56, CD 6, CD 74, CD 80, CS1 (cell-surface glycoprotein 1, cell surface glycoprotein 1), CTLA4 (Cytotoxic T-Lymphocyte Antigen 4, aka: CD152, cytotoxic T lymphocyte antigen 4), DR5 (death receptor 5, cell death receptor 5), Ep-CAM (Epithelial ceU Adhesion Molecule, epithelial cell adhesion molecule), folate receptor alpha receptor Alpha folate, GD2 ganglioside, GD3 ganglioside, GPIMMB, NMB glycoprotein, HGF / SF (hepatocyte growth factor / scatter factor, hepatocyte growth or dispersion factor), IGF-1 (insulin-like growth factor, growth factor similar to insulin), IGF1 receptor (insulin-like growth factor-1 receptor, insulin-like growth factor receptor), IL 13 (interleukin-13), IL 6 (interleukin-6), IL-6R (interleukin-6 receptor, interleukin-6 receptor), fungal immunodominant antigen heat shock protein 90 (hsp90), alpha-5 integrin beta 3, the major histocompatibility complex (MHC) class II or major type II histocomparability complex, MN-antigen (also called G250-antigen, MN or G250 antigen), MUC1, PD-I (programmed death 1 , programmed death protein 1), PIGF (Placental Growth Factor, PDGFRa (platelet-derived growth factor receptor alpha, alpha receptor for platelet-derived growth factor), prostate-specific antigen membrane, (PSMA, Prostate membrane-specific antigen), PTHrP (parathyroid hormone related protein, parathyroid hormone-like protein), CD200 receptor, receptor activator of nuclear factor kappa B ligand (RANKL, factor activator receptor ligand nuclear kappa B), the sphingos ine-1-phosphate (SlP), the

TGF beta, (transforming growth factor beta), the TRAIL (tumor necrosis factor (TNF) -related apoptosis-inducing ligand) receptor 1, (receptor 1 of the ligand inducing apoptosis by TNF), tumor necrosis factor receptor 2, vascular endothelial growth factor receptor 2 (VEGFR-2, vascular endothelial growth factor receptor 2), CD 33, CD 20, CA125 (Cancer 125 antigen, 125 cancer antigen) or the Epidermial growth factor receptor (Epidermal Growth Factor Receptor).

18. Composition according to claim 17, characterized in that the antibody is chosen from the group of antibodies comprising alemtuzumab, bevacizumab, cetuximab, efalizumab, gemtuzumab, britumomab, ovarex mab, panitumumab, rituximab, tositumomab and trastuzumab.

19. Composition according to one of claims 1 to 15, characterized in that the antibody is chosen from the group of antibody or antibody fragments used in dermatology, with the target: - TNF alpha, (tumor necrosis factor alpha, tumor necrosis factor alpha), IL 12, TNF alpha, (tumor necrosis factor alpha, tumor necrosis factor alpha), IL 15, IL 8, interferon alpha, CD 3, TNF alpha, (tumor necrosis factor alpha or necrosis factor alpha tumors).

20. Composition according to claim 19, characterized in that the antibody is chosen from the group of antibodies comprising adalimumab, IΑBT874, etanercept, IΑMG714, HuMax-IL8, MEDI545, otelixizumab and infliximab. .

21. Composition according to one of claims 1 to 16, characterized in that the antibody is selected from the group of antibodies or antibody fragments used in respiratory and pulmonary diseases with the target:

IL 4 and 13, IL 13, IL 5 receptor, IL 1 interleukin 1, IL 13, tumor necrosis factor receptor 1 (TNFR1, tumor necrosis factor receptor 1) ), CD 25 (cluster of differentiation 25, cluster of differentiation 25), CTGF (Connective Tissue Growth Factor, TNF alpha),

(tumor necrosis factor alpha, tumor necrosis factor alpha), GM-CSF (granulocyte monocyte colony stimulating factor, granulocyte colony stimulating factor), CD 23, RSV, Respiratory Syncitial Virus l IL 5, IL 13, Staphylococcus aureus dumping factor A, tissue factor, IgE, immunoglobulin E or Respiratory Syncitial Virus-Respiratory Syncytial Virus (RSV) syncytial).

22. Composition according to claim 21, characterized in that the antibody is chosen from the group of antibodies comprising IΑMG317, Anti-IL13, BIW-8405, canakinumab, CAT354, CNTO148, Daclizumab, FG. -3019, GC-1008, golimumab, KB002, lumiliximab, MEDI557, mepolizumab, QAX576, tefibazumab, TNX-832, omalizumab and palivizumab

23. Composition according to one of Claims 1 to 16, characterized in that the antibody is chosen from the group of antibodies or antibody fragments used in autoimmune and inflammatory diseases, chosen from the antibodies targeting:

- TNF alpha (tumor necrosis factor alpha, tumor necrosis factor alpha), CD 25 (cluster of differentiation 25, differentiation cluster 25), CD, LFA-I (lymphocyte function-associated antigen, antigen associated with functions lymphocytes), CD3, IgE (immunoglobulin E), HL6, B7RP-1 (B7 related protein, protein similar to B7 protein), Blys (B lymphocyte stmulator, B cell stimulator), CCR4 (Chemokine CC receptor 4, CC chemokine receptor 4), CD IIa, CD 20 (cluster of differentiation 20, cluster of differentiation 20), CD 22 (cluster of differentiation 22, cluster of differentiation 22), CD 23 , CD 4, CD 40, CD 44, CD 95, CXCL10, eotaxin 1, GM-CSF (granulocyte monocyte colony stimulating factor, granulocyte colony stimulating factor), HL 1 (interleukin 1 ), 11 L

12, IL 13, IL 15, IL 18, IL 5, HL 8, HL12, HL 23, the integrin alpha 4 beta 7, the integrins alpha 4 beta 1 or alpha 4 beta 7 alpha interferon, interferon gamma, interleukin-17 receptor, receptor activator of nuclear factor kappa B ligand (RANKL, kappa B nuclear factor activator receptor ligand), VAP-I (vas

Protein-1 adhesion) inflammation receptor (vascular adhesion protein-1 receptor inflammation) or VAP-I (vascular adhesion protein-1, vascular adhesion protein 1).

24. Composition according to claim 23, characterized in that the antibody is chosen from the group of antibodies comprising adalimumab, basiliximab, daclizumab, efalizumab, muromonab-CD3, omalizumab and tocilizumab.

25. Composition according to one of claims 1 to 16, characterized in that the antibody is selected from the group of antibodies or antibody fragments used in cardiovascular and circulatory diseases targeting: - the glycoprotein Ilb / IIIa receptor of human platelets, human platelet glycoprotein Ilb / IIIa, oxidized low density lipoprotein (oxLDL, oxidized low-density lipoprotein), digoxin or factor VIII.

26. Composition according to claim 24, characterized in that the antibody is selected from the group of antibodies comprising abciximab, 7E3, BI-204, Digibind and TB402.

27. Composition according to one of Claims 1 to 16, characterized in that the antibody is chosen from the group of antibodies or antibody fragments used in diseases of the central nervous system that target:

CD 52, integrins alpha 4 beta 1 or alpha 4 beta 7, IL

12, beta amyloid peptide, IL 12, IL 23, CD 25 (cluster of differentiation 25- differentiation cluster 25), myelin associated glycoprotein (MAG, myelin-associated glycoprotein, CD 20, or NGF (neural growth factor).

28. Composition according to claim 27, characterized in that the antibody is chosen from the group of antibodies comprising alemtuzumab, natalizumab, IΑBT874, Bapineuzumab, CNTO 1275, Daclizumab, GSK249320, rituximab, and RN624.

29. Composition according to claim 25, characterized in that the antibody is chosen from the group of antibodies comprising one of claims 1 to 14, characterized in that the antibody is chosen from the group of antibodies or antibody fragments used. in gastrointestinal diseases that target: TNF alpha (tumor necrosis factor alpha, tumor necrosis factor alpha), CD 25 (cluster of differentiation 25, cluster of differentiation 25), toxin A of Clostridium difficile, CXCL10, IL5 or integrins alpha 4 beta 1 or alpha 4 beta 7.

30. Composition according to claim 29, characterized in that the antibody is chosen from the group of antibodies comprising infliximab, adalimumab, basiliximab, CNTO148, golimumab, MDX066, MDX1100, mepolizumab, MLN02. and Reslizumab.

31. Composition according to one of Claims 1 to 16, characterized in that the antibody is chosen from the group of antibodies or antibody fragments used in infectious diseases, chosen from the antibodies targeted at: - Protein d envelope 2 of the hepatitis C virus, the PS

(PhosphatidylSerine, phosphatidylserine), lipoteichoic acid, penicillin-binding protein (PBP protein binding to penicillin), CD4, CTLA4 (Cytotoxic T-Lymphocyte Antigen 4, aka: CD152, cytotoxic T lymphocyte antigen 4 )), PD-1 (programmed death 1, programmed death protein 1), West NiIe Virus, West Nile virus), Fungal antigen heat shock protein 90 (fungus heat shock protein 90), CCR5 (Chemokine CC receptor 5, CC chemokine receptor), rabies virus, Bacillus anthracis protection antigen, Staphylococcus aureus dumping factor A, Stx2 or IeNF alpha, (tumor necrosis factor alpha, necrosis factor of alpha tumors).

32. Composition according to claim 31, characterized in that the antibody is chosen from the group of antibodies comprising Bavituximab PEREGRINE, BSYXA110, cloxacillin, ibalizumab, MDX010, MDX1106, MGAWNl, Mycograb, Prol40, Rabies Antibody, raxibacumab, tefibazumab and TMA15.

33. Composition according to one of claims 1 to 16, characterized in that the antibody is selected from the group of antibodies or antibody fragments used in metabolic diseases and endocrinology targeting: - CD 3, l IL-1 (interleukin 1), GCGR (glucagon receptor, glucagon receptor), PTHrP (parathyroid hormone related protein, protein similar to parathyroid hormone) or CD 3.

34. Composition according to claim 31, characterized in that the antibody is chosen from the group of antibodies comprising I1OR-T3, IΑMG108, IΑMG477, CAL, canakinumab, otelixizumab, Teplizumab and XOMA052.

35. Composition according to one of claims 1 to 16, characterized in that the antibody is selected from the group of antibodies used in the female metabolic diseases targeted at:

36. Composition according to claim 35, characterized in that the antibody is chosen from the group of antibodies comprising Denosumab.

37. Composition according to one of the preceding claims, characterized in that the antibody is bevacizumab.

38. Composition according to one of the preceding claims, characterized in that the antibody is cetuximab.

39. Pharmaceutical formulation comprising a composition according to any one of claims 1 to 16 wherein the molar ratio polysaccharide / antibody of between 0.2 and 20, preferably between 0.5 and 10.

40. Process for optimizing the stabilization of a formulation of a monoclonal antibody comprising the steps of: - a monoclonal antibody is available

the library of amphiphilic polymers comprising the polysaccharides defined above is available

the thermal stabilization of said antibody is measured; the amphiphilic polysaccharide (s) capable of providing the best stabilization at the concentrations of the pharmaceutical formulations are determined;