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

20230293636 ยท 2023-09-21

    Inventors

    Cpc classification

    International classification

    Abstract

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

    Claims

    1. An anti-IL-6 agent for use in a method of preventing or treating post-operative pain in an individual.

    2. The anti-IL-6 agent for use according to claim 1, wherein the anti-IL-6 agent is an immunotherapeutic agent.

    3. The anti-IL-6 agent for use claim 1, wherein the anti-IL-6 agent is a passive immunotherapy agent.

    4. The anti-IL-6 agent for use claim 1, wherein the anti-IL-6 agent is an anti-IL-6 or anti-IL-6R antibody, in particular monoclonal antibody, or an IL-6 or IL-6R binding portion of an antibody.

    5. The anti-IL-6 agent for use claim 1, wherein the anti-IL-6 agent is an active immunotherapy agent.

    6. The anti-IL-6 agent for use claim 1, wherein the anti-IL-6 agent comprises, or consists of, a polypeptide derived from IL-6 or the IL-6 receptor (IL-6R), optionally bound to a carrier protein.

    7. The anti-IL-6 agent of 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 thereto.

    8. The anti-IL-6 agent for use according to claim 1, wherein the agent is selected from the group consisting of an IL-6 receptor or an IL-6 binding portion thereof or an anti-IL-6 aptamer.

    9. The anti-IL-6 agent for use claim 1, wherein post-operative pain is not immediate.

    10. The anti-IL-6 agent for use claim 1, wherein the post-operative pain is subsequent to arthroplasty, in particular of the knee or hip, thoracic surgery, in particular cardiac surgery, thoracotomy or sternotomy, breast surgery, hernia surgery, hysterectomy, cholecystectomy, arthroscopy of the knee, or caesarean section.

    Description

    DESCRIPTION OF THE FIGURES

    [0074] FIG. 1 FIG. 1 plots the force-applied paw withdrawal threshold of a mouse (y-axis, in g force) as a function of time since paw incision (x-axis, in days) for mice injected with PBS (controls, stars), anti-IL-6 antibody (passive immunization, squares), or not incised (controls, triangles).

    [0075] FIG. 2 FIG. 2 plots the force-applied paw withdrawal threshold of a mouse (y-axis, in g force) as a function of time since paw incision (x-axis, in days) for mice injected with PBS (controls, stars), IL-6-derived peptide (active immunization, squares), or not incised (controls, triangles).

    EXAMPLES

    [0076] The inventors used a mouse model that measures post-operative pain and is known to be a good model of surgery-related pain (Pogatzki et al. (2003) Anesthesiology 99:1023-7: Cowie et al. (2019) Bio Protoc. 9:e3140). This model is interesting for exploring immediate post-operative pain but also chronic pain as the latter has often been associated with inadequate treatment of the former (Pogatzki-Zahn et al. (2017) Pain Rep. 2:e588).

    Method

    [0077] Briefly, mice under anesthetic inhalation have a skin and muscle incision of about 5 mm in the sole of the foot of the hind leg (the incision starts in front of the heel towards the toes of the foot). The incision is made in two steps, first the skin and then the flexor digitorum brevis muscle after lifting the latter with a curved forceps. The wound is then sutured (5.0 nylon thread) in two points at the skin level. The sutures are removed on the fourth day.

    [0078] The pain sensitivity tests performed in mice by the inventors are mechanical push tests at the plantar level just at the heel 3 mm from the tip of the incision. Calibrated von Frey filaments corresponding to a force of 0.07 g, 0.16 g, 0.4 g, 0.6 g, 1 g. 1.4 g, and 2 g (i.e. a force of 0.68 to 19.6 mN) are used. Each filament is applied 5 times for about 1 s, with an interval of 10s between each application, starting with the smallest force, then increasing. A withdrawal of the paw following a pressure is considered as a signal, and when there were least 3 withdrawals on the 5 trials with the same filament, it is considered that there is sensitivity to the considered force. The first filament inducing at least 3 withdrawals out of 5 trials corresponds to the mechanical sensitivity threshold of a mouse. If no filament induces a withdrawal, the sensitivity threshold is considered to be 4 g force (39.2 mN), which corresponds to the filament of size greater than that of 2 g force. Sensitivity is measured every day for 7 days starting from the day after incision.

    [0079] Groups of 6 mice treated with anti-IL-6, not treated with anti-IL-6, incised or not incised are compared.

    [0080] Two types of treatment were evaluated in this model of post-operative 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

    [0081] 18 adult male C3H/He mice of 20-30 g were divided into 3 groups: [0082] 12 mice to be incised receiving PBS (6 mice, group 1) or anti-IL-6 antibody (6 mice, group 2) by intraperitoneal (ip) injection one day before incision; [0083] 6 mice (group 3) receiving PBS in ip injection and which will follow the operative protocol but will not be incised (anesthesia and awakening, without incision). PBS is injected ip in 0.3 mL.

    [0084] 0.5 mg of the polyclonal anti-IL-6 antibody (R&D systems, ref AF406 NA) is dissolved in 1 mL of PBS and 0.3 mL of the mixture is injected by the ip route.

    [0085] The results of the mechanical sensitivity tests (thresholds obtained) for mice in the 3 groups are summarized in FIG. 1, where the points correspond to the group means with standard deviations:

    Example 2 - Active Immunization

    [0086] 18 adult male C3H/He mice of 20-30 g were divided into 3 groups: [0087] 12 mice immunized against KLH carrier protein alone (6 mice, group 1) or against an IL-6-derived peptide coupled to KLH (6 mice, group 2) immunized at D0, D15, D45, and D75 before incision at D80 ; [0088] 6 mice immunized against the KLH carrier protein (6 mice, group 3) immunized at D0, D15, D45, and D75 that will follow the surgical protocol at D80 without being incised (anesthesia and awakening without incision).

    [0089] Immunizations are performed by subcutaneous injection in the upper back of the mouse of 100 .Math.L of ISA51 mixed with 100 .Math.L of KLH protein (amount 80 .Math.g) for groups 1 and 3, and mixed with 100 .Math.L of KLH (amount 80 .Math.g) covalently coupled to the murine IL-6_200 peptide (amount 40 .Math.g) for group 2. The murine IL-6-200 peptide coupled to KLH has the sequence: CMNNDDALAENNLKLPECY (SEQ ID NO: 2) (cyclized by C-C bond) and was previously described in Desallais et al. (2014) Arthritis Research & Therapy 16:R157.

    [0090] The results of the mechanical sensitivity tests (thresholds obtained) for mice in the 3 groups are summarized in FIG. 2, where the points correspond to the group means with standard deviations.

    [0091] In both Examples, it can be seen that treatment with an anti-IL-6 antibody, as well as treatment with active anti-IL-6 immunotherapy, lead to significantly less pain sensitivity in the anti-IL-6 treated mice.