EP4084818A2

EP4084818A2 - Pharmaceutical composition for the prevention or treatment of post-surgical pain

Info

Publication number: EP4084818A2
Application number: EP20845576.6A
Authority: EP
Inventors: René AZOULAI; Xavier CASSARD; Jean-Pierre Salles; Jean-François ZAGURY
Original assignee: Peptinov
Current assignee: Peptinov
Priority date: 2019-12-31
Filing date: 2020-12-31
Publication date: 2022-11-09
Also published as: CA3163270A1; US20230293636A1; AU2020418554A1; WO2021136841A2; WO2021136841A3; JP2023508592A

Abstract

The invention relates to an anti-IL-6 agent for use in a method of preventing or treating post-surgical pain in a subject.

Description

PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF POST-OPERATIVE PAIN

Field of the invention

The present invention relates to a pharmaceutical composition useful for the prevention or treatment of postoperative pain, in particular persistent or chronic.

Technical background

Surgical interventions are very often followed by immediate and medium-term, or even chronic, post-operative pain. It is thus noted that for certain operations, chronic pain can persist for more than a year with rates exceeding 20% for knee replacements or even 40% for cardiac surgeries. The persistence of these pains and their intensity can significantly impact the quality of life of patients and also their professional activity, and this poses a major public health problem.

Several approaches have been explored to reduce immediate postoperative pain, but very few studies have focused on chronic postoperative pain despite their significant morbidity.

For many operations, such as knee arthroplasty, for example, in a significant proportion of patients, pain persisting over several months and sometimes several years has been shown, often associated with a significant drop in quality of life. patients.

Few approaches have been tested to prevent this type of prolonged pain. Apart from † recognized risk factors such as depression or the intensity of preoperative pain, it has been described that chronic pain may in part result from insufficient treatment of immediate postoperative pain (Poga † zki-Zahn et al. al. (2017) Pain Rep. 2: e588; Searle & Simpson (2010) Continuing Education in Anaesthesia Critical Care & Pain 10: 12-14).

It therefore remains necessary to identify useful agents for the management of postoperative pain, in particular chronic pain. Summary of the invention

The present invention stems from the unexpected demonstration, by the inventors, that, in the murine skin-muscular incision model, the post-operative pain was significantly reduced thanks to the blocking of IL-6 that it does † by administration of anti-IL-6 antibodies or by administration of active anti-IL-6 immunotherapy.

Thus, the present invention relates to an agent an † i-IL-6 for use in a method of preventing or treating one or more postoperative pain, in particular chronic, in an individual.

The present invention also relates to a method of preventing or treating postoperative pain, in particular chronic pain, in an individual, in which the individual is administered a prophylactically or therapeutically effective amount of an anti-IL-6 agent. .

The present invention also relates to the use of an anti-IL-6 agent for the preparation of a medicament, a vaccine or a pharmaceutical composition intended for the prevention or treatment of postoperative pain, in particular chronic, in an individual.

In a preferred embodiment of the invention, the anti-IL-6 agent is combined with at least one other anti-IL-6 agent.

As a preliminary point, it will be recalled that the term “comprising” means “including”, “containing” or “encompassing”, that is to say that when an object “comprises” an element or several elements, other elements that those mentioned can also be included in the object. Conversely, the expression "consisting of" means "constituted of", that is to say that when an object "consists of" an element or several elements, the object cannot include other elements. than those mentioned.

Post-operative pain

As understood here, postoperative pain according to the invention is pain following a surgical operation. Preferably, the postoperative pain according to the invention is not immediate, that is to say it does not appear at the end of the operation, in particular when the individual wakes up. having undergone the operation if the latter was put to sleep for the operation.

Preferably, the postoperative pain according to the invention is not acute.

Preferably, the postoperative pain according to the invention is chronic pain. Preferably, the postoperative pain according to the invention is persistent pain, in particular pain which persists for more than 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 6 months or 1 year after the treatment. surgery.

Preferably, the post-operative pain according to the invention is consecutive to an arthroplasty, in particular of the knee or of the hip, to a thoracic operation, in particular a cardiac operation, a thoracotomy or a sternotomy, a breast operation, a breast surgery. hernia operation, hysterectomy, cholecystectomy, knee arthroscopy, or cesarean section.

Agent

Interleukin 6 (IL-6), also sometimes called B-cell stimulating factor 2 (B-cell sfimulafory factor 2, BSF-2), cytotoxic T lymphocyte differentiation factor (CTL differentiation factor, CDF), growth of hybridomas, or interferon b-2 (IFN-p-2) is well known to those skilled in the art. Numerous IL-6 sequences from various animal species are available in sequence databases. By way of example, a human IL-6 is described in the UniProt / Swissprot database under the reference P05231 (SEQ ID NO: 1). By way of example also the alpha subunit of the human IL-6 G receptor is described in the UniProt / Swissprot database under the reference under the reference P08887 (SEQ ID NO: 4).

As understood here, an anti-IL-6 agent is an agent capable of blocking, in part or in whole, the action of IL-6 in vivo or in the body.

The anti-IL-6 agent according to the invention can be of any type. It can in particular be a protein, a nucleic acid or a small molecule.

Preferably, the anti-IL-6 agent according to the invention is specifically directed against IL-6 or else against the IL-6 receptor in order to block the IL-6 pathway.

Preferably, the anti-IL-6 agent according to the invention is an immunotherapeutic agent. More preferably, the anti-IL-6 agent according to the invention is a passive immunotherapy agent. Even more preferably, the anti-IL-6 agent according to the invention is an antibody, in particular monoclonal, anti-IL-6 or a part of antibody binding to IL-6.

More preferably also, the agent is selected from the group consisting of an IL-6 receptor or an IL-6 binding part thereof or an anti-IL-6 aptamer. .

Anti-IL-6 agents, including antibodies, antibody fragments, receptors, receptor moieties, and aptamers, according to the invention, are said to be specifically directed against IL-6 when they exhibit substantially no binding to. another polypeptide, which does not comprise G IL-6, under conditions allowing the binding of the antibodies, antibody fragment, and aptamers according to the invention to IL-6.

The antibody according to the invention can be polyclonal or monoclonal, preferably monoclonal. By way of example of a monoclonal anti-IL-6 antibody according to the invention, mention may be made of tocilizumab or clazakizumab. Moreover, as understood here, the “antibody fragments” comprise at least one antigen-binding part of the antibody from which they are derived, and are in particular of the Fab, Fab ', F (ab ') 2, Disulfide stabilized Fv (dsFv), dimerized (diabody), trimerized, tetramerized or pentamerized V region, single chain Fv (scFv), complementarity determining region (CDR).

The antibodies can be of any species, in particular human, mouse, rat, rabbit or camelid. On the other hand, when they are not human, they can also be humanized, that is, the constant parts of these antibodies are replaced partially or entirely by corresponding constant parts human.

The antibodies according to the invention can be obtained by immunizing an animal with the aid of a polypeptide according to the invention according to techniques well known to those skilled in the art.

As understood here, aptamers are nucleic acids, especially RNAs, capable of specifically binding to a molecular target, such as a protein. The aptamers can in particular be obtained by implementing the SELEX technique well known to those skilled in the art, from the polypeptides according to the invention.

Alternatively, the anti-IL-6 agent according to the invention is more preferably an active immunotherapy agent. Still, more preferably, the anti-IL-6 agent comprises, or consists of a polypeptide derived from IL-6 or the IL-6 receptor (IL-6R), optionally attached to a carrier protein. Preferably, the polypeptide comprises, or consists of, a sequence of at least 6 amino acid residues of IL-6 or IL-6R or a variant sequence having at least 90% identity with this one.

The polypeptide according to the invention can in particular be as described in international application WO2013 / 021284, which is incorporated here by reference.

Preferably, the polypeptide according to the invention comprises at least the sequence ALAENNL (SEQ ID NO: 3) or a sequence having at least 90% of sequence identity with SEQ ID NO: 3.

More preferably, the polypeptide according to the invention comprises or consists of CMNNDDALAENNLKLPECY (SEQ ID NO: 2), CESSKEALAENNLNLPKC (SEQ ID NO: 5), CESSKEALAENNLNLPKCY (SEQ ID NO: 6), or a sequence having at least 90% sequence identity with SEQ ID NO: 2, 5 or 6.

Preferably, the variant sequence according to the invention has at least 95% or 98% identity with the sequence according to the invention.

As understood here, the percentage identity between two peptide sequences can be determined by performing an optimal alignment along the entire length of the sequences, by determining the number of aligned positions for which the amino acids are identical in each sequence. and dividing that number by the total number of amino acids in the longer of the two sequences. The optimal alignment is the one that gives the highest percentage of identification between the two sequences.

The variant sequence according to the invention is † such that a polypeptide consisting of the variant sequence must make it possible to elicit an immune response directed against IL-6; that is to say that the administration of such a polypeptide, optionally cyclized by formation of at least one inter-cysteine disulfide bridge, if necessary after addition of one or two cysteines within the polypeptide, and / or at its N-terminus and / or at its C-terminus, the polypeptide optionally being linked to a carrier molecule, in particular a carrier protein, such as KLH (Keyhole Limpe † Hemocyanin), to an animal, such as a mouse, ra † or rabbit, causes the production of antibodies against IL-6. Those skilled in the art know how to determine whether an antibody is directed against IL-6, in particular by carrying out an ELISA test. Preferably, the antibodies elicited by administration of polypeptide are blockers or neutralizers, that is to say they prevent IL-6 from exerting all or part, in particular at least 10%, 25%, 50%, 75%, of its activity, for example measured in vitro.

The polypeptide according to the invention preferably comprises at most 200, 150, 100, 90, 80, 70, 60, 50, 40 or 30 amino acid residues. Alternatively, the polypeptide can be IL-6.

As will be clear to those skilled in the art, the polypeptide according to the invention can comprise several repeats, for example 2, 3, 4, 5, 10 or 20 repeats, respectively of the sequence or of the variant sequence according to the invention.

Furthermore, the polypeptide according to the invention can also include additional sequences not originating from IL-6.

These additional sequences could in particular provide physicochemical characteristics allowing improved structural presentation or improved solubility of the polypeptide according to the invention compared to a similar polypeptide but which will not include these additional sequences.

The additional sequences can also comprise one or more peptide link sequences, that is to say linker peptide sequences, useful for binding in particular to a carrier molecule. Such peptide link sequences typically comprise from 1 to 10, especially 4 to 6, amino acid residues. Moreover, these sequences, not originating from IL-6, can also include epitopes belonging to other proteins, making it possible to elicit or generate an immune response directed against these other proteins.

In addition, the polypeptide according to the invention may contain sequences of exogenous T epitope (s), preferably universal (s), which makes it possible to reinforce the immunogenicity of the polypeptide according to the invention.

The polypeptide according to the invention can also include at least one sequence of a carrier protein, for example a virus-like particle (VLP), as described in particular in international application WO 05/1 17983 for TNF.

The polypeptide according to the invention can be in linear form or in cyclized form. Preferably, the polypeptide according to the invention is in cyclized form. This cyclization can be of a crazy type known to the man of the mistrust. The choice of the cyclization strategy according to the invention can in particular take into account the best antigenic presentation of the epitopes contained in the polypeptide according to the invention, and relate only to part of the polypeptide (cyclization within the sequence). Thus, as understood here, when the polypeptide according to the invention is in cyclized form, only part of the polypeptide can be included in a cycle while the rest of the polypeptide is in linear form.

Depending on the functional groups present in the polypeptide, this †† cyclization can be carried out in several different ways, such as for example: from its C-terminus to N-terminus, from its N-terminus to a chain side, of a side chain at its C-terminal end or between two side chains. Among the various modalities of polypeptide cyclization, it is possible to cite lactamization, lactonization or the formation of a pon † disulfide. In particular, during the formation of an inter-cysteine pon † disulfide, that is to say between the -SH radicals of two cysteines, the cysteines may already be present in the variant sequence according to the invention or in the first, second, third, fourth e † fifth sequences according to the invention, or else be added within these sequences, as well as at their N-terminal and / or C-terminal end.

In addition, the polypeptide according to the invention can include pos † - translational modifications, such as glycosylations, methylations, acylations, in particular by fatty acids, or phosphorylations. In particular, the N-terminal end of the polypeptide according to the invention can be acetylated and the C-terminal end can be modified by amidation.

The polypeptide according to the invention may also include one or more analogues or derivatives of amino acids, don † unnatural or non-standard amino acids, in particular norleucine (Nie).

Also preferably, the polypeptide according to the invention is attached or linked, in particular by covalent bonding, to a carrier protein.

In particular, the carrier molecule may be the Keyhole Limpe † Hemocyanin (KLH) protein, hepatitis B surface antigen (HBsAg), bovine serum albumin (BSA), tetanus toxoid (TT) and † diphtheria toxoid (DT).

The diphtheria toxoid (DT) according to the invention is preferably chosen from the group consisting of CRM 197, CRM 176, CRM 228, CRM 45, CRM 9, CRM 102, CRM 103, e † of CRM 107. Particularly preferably, the carrier molecule is CRM 197.

The binding of the polypeptide according to the invention to a carrier molecule, in particular a carrier protein, can be carried out using a heterobifunctional coupling agent, such as the ester of Ng-maleimidobutyryl-oxysuccinimide (GMBS) e † sulfo-GMBS derivative, m-maleimidobenzoyl-n-hydroxysuccinimide ester (MBS) e † sulfo-MBS derivative, succinimidyl 4- (N-maleimidome † hyl) cyclohexane-l -carboxylate (SMCC), a carbodiimide , bisdiazonium-benzidine (BDB) or glutaraldehyde When GMBS, MBS or SMCC are used, they are preferably attached to a cysteine (C), which if not present in the sequence, or the variant sequence according to the invention, can be added, in particular at its N-ferminal or C-ferminal end. Moreover, when a cysteine is present in the sequence according to the invention at an undesired position, it is possible to implement, instead, a variant sequence in which the cysteine is substituted by another acid. amine, such as a serine.

When the BDB is used, it is preferably attached to a tyrosine (Y), which if it is not present in the sequence or the variant sequence according to the invention, can be added, in particular at its end. N-ferminal or C-terminal. Furthermore, when a tyrosine is present in the sequence according to the invention at an undesired position, it is possible to implement, instead, a variant sequence in which the tyrosine is substituted by another acid. amino, such as phenylalanine (F)

Furthermore, the binding of the polypeptide according to the invention to a carrier molecule, in particular a carrier protein, can also be carried out using a peptide link or peptide linker, which is linked † to the polypeptide according to the invention. 'one side e † to the carrier molecule on the other side, optionally via a heterobifunctional coupling agent as defined above. Such peptide bonds typically comprise from 1 to 10, especially 4 to 6, amino acid residues.

Individual

Preferably, the individual according to the invention is a mammal, in particular a human, a dog, a cat or a horse.

When the individual according to the invention is a human, it can be a man, a woman, or a child. Preferably, the individual according to the invention is a human aged over 40, 50, 60 or 70 years.

As will easily be understood, the individual according to the invention has undergone, or must undergo, a surgical operation, in particular likely to produce postoperative pain according to the invention.

Method

Preferably, the method of preventing or treating postoperative pain according to the invention is a method of passive immunotherapy, in particular serotherapy, or a method of active immunotherapy, in particular vaccine therapy.

Alternatively, the method according to the invention is a method of administering a small molecule targeting the IL-6 pathway at regular intervals, in particular every day, every other day, or every three days.

Administration

The anti-IL-6 agent according to the invention is preferably administered or in a form which can be administered by the oral, mucosal, in particular sublingual, parenteral, intraperitoneal, transcutaneous, intradermal, subcutaneous, intramuscular, intravenous or intraarterial route. .

The anti-IL-6 agent according to the invention is preferably in an oral dosage form, in particular in the form of a tablet, capsule, syrup, powder to be dissolved, solution or oral suspension; injectable, especially in the form of solution in ampoule, syringe or pen, powder to dissolve, solution for slow infusion; dermal, in particular in the form of an ointment, cream, gel, solution, powder to be dissolved or patch; inhaled, especially in the form of an aerosol; or rectal, in particular in the form of a suppository.

When the anti-IL-6 agent is a polypeptide according to the invention, it can be administered at doses ranging, for example, from 1 ng to 1 g, preferably from 1 g to 1 mg.

When the anti-IL-6 agent is an antibody, especially monoclonal, the amounts administered may be of the order of 0.5 to 30 mg / kg.

When the agent is a small molecule, it can be administered in doses ranging for example from 50 µg up to 5 g per administration. The an † i-IL-6 agent can be combined with at least one pharmaceutically acceptable vehicle within a medicament or a pharmaceutical or vaccine composition. As understood here, a “pharmaceutically acceptable vehicle” includes all the compounds, in particular the excipients, which can be administered to an individual in conjunction with a pharmacological active principle. Moreover, in particular when it is used in a vaccine or prophylactic context, the polypeptide according to the invention can be associated or combined with an adjuvant, or the pharmaceutical or vaccine composition, or the drug according to the invention can include a adjuvant. The adjuvant can be of any type suitable for increasing the immune response of an individual, animal or human, to the administration of a polypeptide. It can thus be complete or incomplete Freund's adjuvant, Montanide ISA 51 VG, aluminum hydroxide, aluminum phosphate or calcium phosphate for example; Montanide ISA 51 VG e † aluminum hydroxides or aluminum phosphate being preferred. The adjuvant can be combined with the polypeptide according to the invention by producing a 1 / L mixture by volume of a solution of adjuvant and of a solution comprising the polypeptide.

The individual may be given agent anfi-IL-6 before or immediately after their operation. This administration can typically be done by regular injections or tablets, until the individual is no longer in pain, two months before the operation, preferably less than a month before the operation, possibly a few months before the operation. days before the operation, possibly after the operation but less than 3 months after its completion. The spacing between administrations will depend on the pharmacology of the product. Thus if it is an antibody, in particular monoclonal, administration can typically be done every 15 days or every month until the end of the postoperative pain, with a start for example in the month preceding the operation. If it is a small molecule, the taking of the pharmaceutical composition or the drug comprising it, for example in the form of a tablet, will normally be done more frequently as is often the practice for small e † pharmaceutical molecules may start a few days before or after the operation, in particular from 15 days before until 15 days after the operation.

In the case of active immunization, it will be preferable that the immunization begins several weeks before the operation so that antibodies can be generated and effective as soon as the operation is performed. Typically, the individual could be immunized 3 months before the operation, with boosters every 3 weeks, until a rate of satisfactory antibody has been induced. Nothing prevents immunization closer to the operation, or even after the operation.

Combination

As used herein the expression "in combination" or "combined" means that the agent an † i-IL-6 and the other agent an † i-IL-6 as defined above can be associated within the same pharmaceutical composition or the same drug, e † therefore be administered together, or be administered separately, that is to say according to separate routes of administration and / or regimens separate administration, provided that when administered separately the periods of prophylactic or therapeutic activity of the agent an † i-IL-6 e † of the other agent an † i-IL-6 as defined above overlap in whole or in part.

It is preferred, according to the invention, that the an † i-IL-6 agent is a passive immunotherapy agent, such as an antibody or an antibody fragment, or a small molecule, e † that the another an † i-IL-6 agent is an active immunotherapy agent, such as a polypeptide as defined above, and vice versa.

In this context, it is thus possible, according to the invention, to combine the two prevention or treatment approaches with the administration of a compound blocking the IL-6 pathway before or after the operation e † active immunization an † i-IL-6 which could also be done concomitantly or after the administration of a compound directly active against the IL-6 pathway.

The invention will be further explained, in a nonlimiting manner, with the aid of figures e † of the examples which follow.

Fig 1

Figure 1 shows the withdrawal threshold of the paw of a mouse to which a force is applied (y-axis, in g force) as a function of the time elapsed since making an incision on the paw (x-axis , in days) for mice which received an injection of PBS (controls, stars), an antibody an † i-IL-6 (passive immunization, squares), or did not undergo an incision (controls, triangles). Figure 2

FIG. 2 represents the withdrawal threshold of the paw of a mouse to which a force is applied (y-axis, in g force) as a function of the time elapsed since an incision was made on the paw (x-axis, in days) for mice having received an injection of PBS (controls, stars), of a peptide derived from IL-6 (active immunization, squares), or not having undergone an incision (controls, triangles).

EXAMPLES

The inventors used a murine model which makes it possible to measure postoperative pain and which is known to be a good model of pain associated with surgical acts (Pogatzki et al. (2003) Anesthesiology 99: 1023-7; Cowie et al. (Pogatzki et al. (2003) Anesthesiology 99: 1023-7; Cowie et al. ( 2019) Bio Profoc. 9: e3140). This model is interesting for exploring immediate postoperative pain but also chronic pain such as the latter has often been associated with insufficient treatment of the former (Pogafzki-Zahn et al. (2017) Pain Rep. 2: e588).

Method

Briefly, mice under inhaled anesthetic had an approximately 5 mm skin and muscle incision at the sole of the foot of the hind paw (the incision through † in front of the heel towards the toes) . The incision is made in two stages, first the skin and then the flexor flexor muscle of the fingers (or f / exor digiforum brevis) after lifting the latter with a curved forceps. The wound is then sutured (nylon 5.0 thread) at two points on the skin. The sutures are removed on the fourth day.

The pain sensitivity tests carried out in mice by the inventors are tests of mechanical thrust at the plantar level just at the level of the heel, 3 mm from the end of the incision. We use von Frey's calibrated filaments corresponding to a force of 0.07 g, 0.16 g, 0.4 g, 0.6 g, 1 g, 1 .4 g, e † 2 g (assuming a force of 0.68 to 19.6 mN). Each filament is applied 5 times for approximately 1 s, with an interval of 10 s between each application, starting with the smallest force, then gradually. A withdrawal of the paw following a pressure is considered as a signal, e † when there were at least 3 withdrawals out of the 5 tests with the same filament, it is considered that there is sensitivity to the force considered. The first filament inducing at least 3 withdrawals out of the 5 tests therefore corresponds to the threshold of mechanical sensitivity of a mouse. If no filament induces shrinkage, it is considered that the sensitivity threshold is 4 g force (39.2 mN), which corresponds to the filament of size greater than that of force 2 g. Sensitivity is measured daily for 7 days from the day after the incision.

Groups of 6 mice treated per year † i-IL-6, untreated to an † i-IL-6, incised or not incised, were compared. Two types of treatment were evaluated in this model of postoperative pain: administration of an anti-IL-6 antibody (example 1) and active immunization against an immunogenic peptide derived from murine IL-6 (example 2).

Example 1 - Passive immunization.

18 adult male C3H / He mice weighing 20-30 g were divided into 3 groups:

- 12 mice which will be incised receiving PBS (6 mice, group 1) or anti-IL-6 antibody (6 mice, group 2) by intraperitoneal injection (ip) one day before the incision;

- 6 mice (group 3) receiving PBS by ip injection and which will follow the operating protocol but which will not be incised (anesthesia and awakening, without incision).

PBS is injected ip at a rate of 0.3 mL.

0.5 mg of the anti-IL-6 polyclonal antibody (R&D Systems, ref AF406 NA) is dissolved in 1 mL of PBS and 0.3 mL of the mixture is injected ip.

The results of the mechanical sensitivity tests (thresholds obtained) for the mice of the 3 groups are summarized in Figure 1, where the points correspond to the means of the groups with the standard deviations:

Example 2 - Active immunization

18 adult male C3H / He mice weighing 20-30 g were divided into 3 groups:

- 12 mice immunized against the carrier protein KLH alone (6 mice, group 1) or against a peptide derived from IL-6 coupled to KLH (6 mice, group 2) immunized on D0, D 15, D45, and D75 before the incision at D80;

- 6 mice immunized against the carrier protein KLH (6 mice, group 3) immunized on D0, D 15, D45, and D75 which will follow the operating protocol on D80 without being cut (anesthesia and awakening without incision).

The immunizations are carried out by subcutaneous injection in the upper back of the mouse of 100 mί of ISA51 mixed with 100 μL of KLH protein (quantity 80 μg) for groups 1 and 3, and mixed with 100 mί of KLH ( quantity 80 mg) covalently coupled to the murine IL-6_200 peptide (quantity 40 mr) for group 2. The murine IL-6_200 peptide coupled to KLH has the sequence: CMNNDDALAENNLKLPECY (SEQ ID NO: 2) (cyclized by CC bridge ) and has already been described in the publication by Desallais et al. (2014) Arfhrifis Research & Therapy 16: R157. The results of the mechanical sensitivity tests (thresholds obtained) for the mice of the 3 groups are summarized in Figure 2. where the points correspond to the means of the groups with the standard deviations. It can be seen in the two Examples that the treatment with an anti-IL-6 antibody, just like the treatment with active anti-IL-6 immunotherapy, leads to a significantly lower sensitivity to pain for the mice treated with an † i-. IL-6.

Claims

1. Agen † an † i-IL-6 for use in a method of preventing or treating postoperative pain in an individual.

2. Agen † an † i-IL-6 for use according to claim 1, wherein the an † i-IL-6 agent is an immunotherapeutic agent.

3. Agen † an † i-IL-6 for use according to claim 1 or 2, wherein the agen † an † i-IL-6 is a passive immunotherapy agent.

4. Agen † an † i-IL-6 for use according to one of claims 1 to 3, in which the agen † an † i-IL-6 is an antibody, in particular monoclonal, an † i-IL -6 or an † i-IL-6R or part of antibody binding to IL-6 or IL-6R.

5. Agen † an † i-IL-6 for use according to claim 1 or 2, wherein the agen † an † i-IL-6 is an active immunotherapy agent.

6. Agen † an † i-IL-6 for use according to claim 1, 2 or 5, wherein the agen † an † i-IL-6 comprises, or consists of, a polypeptide derived from. IL-6 or IL-6 receptor (IL-6R), optionally attached to a carrier protein.

7. Agen † an † i-IL-6 according to claim 6, wherein the polypeptide comprises, or consists of, a sequence of at least 6 amino acid residues of IL-6 or IL-. 6R or a sequence having at least 90% identity therewith.

8. Agen † an † i-IL-6 for use according to claim 1, wherein the agent is selected from the group consisting of an IL-6 receptor or part thereof. binding to IL-6 or an aptamer an † i-IL-6.

9. Agen † an † i-IL-6 for use according to any one of claims 1 to 8, wherein the postoperative pain is not immediate.

10. Agen † an † i-IL-6 for use according to one of claims 1 to 9, in which the postoperative pain is consecutive to arthroplasty, in particular of the knee or hip, to a thoracic operation including heart surgery, thoracotomy or sternotomy, breast operation, hernia operation, hysterectomy, cholecystectomy, knee arthroscopy, or cesarean section.