Combination therapy of peptide and ivig for treatment of demyelinating disease

Abstract

The present invention relates to a combination therapy for treating demyelinating diseases, and more particularly, to a combination therapy of a peptide consisting of an amino acid sequence represented by SEQ ID NO: 1 and intravenous immunoglobulin (IVIg) for treating demyelinating diseases.

Description

Combination therapy of peptides and IVIG for the treatment of demyelinating diseases

[0001] The present invention relates to a combination therapy of a peptide and intravenous immunoglobulin (IVIg) for the treatment of demyelinating diseases, and more particularly, to a combination therapy of a peptide comprising an amino acid sequence represented by SEQ ID NO: 1 and IVIg for the treatment of demyelinating diseases.

[0002] Most nerve fibers in the nervous system are surrounded by many layers of tissue composed of a lipoprotein called myelin. Myelin acts as an insulator, playing a crucial role in transmitting neural impulses accurately and quickly along the nerve fibers. When this myelin is damaged or destroyed due to local injury, immune disorders, infection, nutritional deficiencies, drugs, or unknown causes, permanent damage is induced to the nerve fibers within. Therefore, when myelin is damaged, the body attempts to repair it through remyelination, but often remyelination fails and demyelination occurs. Diseases caused by this demyelination are called demyelinating diseases.

[0003] Demyelinating disorders occur when the myelin sheath is damaged without significant damage to the nerve cells themselves or their axons. They can occur in both the peripheral and central nervous systems. Symptoms of demyelinating disorders include sensory, motor, and autonomic symptoms, which are further divided into positive and negative symptoms. Negative motor symptoms are caused by conduction block or loss of motor nerve axons and manifest as muscle weakness. Positive motor symptoms, on the other hand, are caused by abnormal activity in the peripheral nerves and manifest as fasciculations, myokymia, tremors, and muscle cramps. Positive sensory symptoms include hypersensitivity, including pain, and dysesthesia, while negative sensory symptoms can include decreased sensation and numbness.

[0004] Currently, medications used for demyelinating diseases primarily address the underlying disease or manage neuropathic pain, a symptom of demyelinating diseases. However, fundamental treatments are rare. For example, treatments for chronic inflammatory demyelinating polyneuropathy (CIDP), a type of demyelinating disease, include steroids (primarily prednisone), intravenous immunoglobulin (IVIg), and plasma exchange.

[0005] IVIg is a treatment that administers high doses of purified immunoglobulin G (IgG) from the plasma of healthy donors. However, it has drawbacks such as high cost, inconvenience of repeated administration, and limited therapeutic response in some patients. Therefore, there is a need for a treatment strategy that overcomes the limitations of existing monotherapy and provides improved therapeutic effects through combination therapy of IVIg.

[0006] Accordingly, the present inventors have endeavored to develop a treatment regimen that has an effective therapeutic effect while minimizing side effects, and as a result, they have manufactured a trimer-type peptide composed of a very small peptide, which can minimize side effects due to the administration of external substances, and confirmed a synergistic effect in improving motor and sensory nerve damage by co-administering the peptide with IVIg in a CIDP animal model. Thus, by revealing that the peptide and IVIg can be usefully utilized in combination therapy for the treatment of demyelinating diseases, the present application has been filed.

[0007] [Prior Art Literature]

[0008] [Patent Document]

[0009] Republic of Korea Publication Patent No. 10-2020-0138904

[0010] [Non-patent literature]

[0011] GGA van Lieverloo et al., Corticosteroids in chronic inflammatory demyelinating polyneuropathy, J Neurol. 2018; 265(9): 2052-2059.

[0012] Vanden Bergh et al., European Academy of Neurology / Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy: Report of a joint Task Force-Second revision, Eur J Neurol. 2021 Nov;28(11):3556-3583.

[0013] An object of the present invention is to provide a combination therapy of peptides and intravenous immunoglobulin (IVIg) for the treatment of demyelinating diseases.

[0014] In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating demyelinating diseases, comprising as active ingredients a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin (IVIg), as a complex, mixed or combined preparation for use in preventing or treating demyelinating diseases.

[0015] In addition, the present invention provides a method for preventing or treating a demyelinating disease, comprising administering to a subject a pharmaceutically effective amount of a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin, in combination, or in combination.

[0016] In addition, the present invention provides the use of a complex, mixed or combined preparation containing as active ingredients a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin, for use as a pharmaceutical composition for preventing or treating demyelinating diseases.

[0017] In addition, the present invention provides the use of a complex, mixed or combined preparation containing as active ingredients a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin, for the manufacture of a pharmaceutical composition for preventing or treating demyelinating diseases.

[0018] In addition, the present invention provides a complex, mixed or combined kit for preventing or treating demyelinating diseases, comprising a preparation comprising a peptide composed of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a preparation comprising intravenous immunoglobulin.

[0019] In the present invention, it was confirmed that a synergistic effect was exhibited in improving motor and sensory nerve damage by co-administering the peptide according to the present invention and intravenous immunoglobulin (IVIg) in a rat model of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Therefore, the peptide and IVIg can be usefully used in combination therapy for treating demyelinating diseases.

[0020] FIG. 1 is a schematic diagram illustrating a method for producing a chronic inflammatory demyelinating polyneuropathy (CIDP) animal model according to one embodiment of the present invention and administering a trimeric peptide KINE-101 according to the present invention and intravenous immunoglobulin (IVIg).

[0021] Figure 2 is a diagram confirming changes in motor nerve conduction velocity (MNCV) following administration of KINE-101 and / or IVIg in a CIDP animal model.

[0022] Figure 3 is a diagram confirming changes in compound muscle action potential (CMAP) following administration of KINE-101 and / or IVIg in a CIDP animal model.

[0023] Figure 4 is a diagram confirming changes in sensory nerve conduction velocity (SNCV) following administration of KINE-101 and / or IVIg in a CIDP animal model.

[0024] Figure 5 is a diagram confirming changes in sensory nerve action potential (SNAP) following administration of KINE-101 and / or IVIg in a CIDP animal model.

[0025] The present invention is described in detail below.

[0026] In the present invention, the term "prevention" means any act of inhibiting or delaying the occurrence, spread, and recurrence of a demyelinating disease by administering the composition of the present invention, and the term "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0027] The present invention provides a pharmaceutical composition for preventing or treating demyelinating diseases, comprising as active ingredients a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin (IVIg), as a complex, mixed or combined preparation for use in preventing or treating demyelinating diseases.

[0028] In addition, the present invention provides a method for preventing or treating a demyelinating disease, comprising administering to a subject a pharmaceutically effective amount of a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin, in combination, or in combination.

[0029] In addition, the present invention provides the use of a complex, mixed or combined preparation containing as active ingredients a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin, for use as a pharmaceutical composition for preventing or treating demyelinating diseases.

[0030] In addition, the present invention provides the use of a complex, mixed or combined preparation containing as active ingredients a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin, for the manufacture of a pharmaceutical composition for preventing or treating demyelinating diseases.

[0031] In addition, the present invention provides a complex, mixed or combined kit for preventing or treating demyelinating diseases, comprising a preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a preparation comprising intravenous immunoglobulin.

[0032] In the present invention, the “peptide” refers to a polymer composed of two or more amino acids linked by amide bonds (or peptide bonds).

[0033] The peptide of the present invention may be composed of an amino acid represented by SEQ ID NO: 1, and may include an amino acid sequence having a sequence identity of 75% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, with the amino acid sequence represented by SEQ ID NO: 1. More specifically, the peptide of the present invention may include an amino acid sequence having a sequence identity of 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or more with the amino acid sequence represented by SEQ ID NO: 1.

[0034] Additionally, the peptide of the present invention may additionally include a targeting sequence, a tag, a labeled residue, an amino acid sequence manufactured for a specific purpose to increase half-life or peptide stability.

[0035] Additionally, the peptide of the present invention can be obtained using various methods widely known in the art. For example, it can be produced using polynucleotide recombination and protein expression systems, in vitro synthesis through chemical synthesis such as peptide synthesis, and cell-free protein synthesis methods.

[0036] Additionally, a protecting group may be attached to the N- or C-terminus of the peptide to obtain better chemical stability, enhanced pharmacological properties (e.g., half-life, absorbability, potency, efficacy, etc.), altered specificity (e.g., broadened biological activity spectrum), or reduced antigenicity. Examples of protecting groups include, but are not limited to, an acetyl group, a fluorenyl methoxy carbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, or polyethylene glycol (PEG).

[0037] Additionally, the peptide of the present invention may be in a pharmaceutically acceptable salt form, specifically, but not limited to, an acetate salt.

[0038] In the present invention, the first preparation and the second preparation may be administered individually, simultaneously, sequentially, or in a time-separated manner.

[0039] Additionally, the first formulation and the second formulation may be administered intravenously. Specifically, the first formulation and the second formulation may be administered intravenously as a single formulation, or may be formulated separately and administered intravenously simultaneously, sequentially, or in a time-staggered manner.

[0040] In addition, in the case where the first preparation and the second preparation are combined into one single preparation, the composition of the present invention may be administered intravenously in a mixing ratio of the first preparation and the second preparation as follows: 1 part by weight of the first preparation: 5 to 100 parts by weight of the second preparation, 1 part by weight of the first preparation: 10 to 70 parts by weight of the second preparation, 1 part by weight of the first preparation: 20 to 60 parts by weight of the second preparation, or 1 part by weight of the first preparation: 30 to 40 parts by weight of the second preparation.

[0041] In addition, in cases where the first preparation and the second preparation are formulated separately, the first preparation and the second preparation in the composition of the present invention may be administered intravenously in combination as 1 part by weight of the first preparation: 5 to 100 parts by weight of the second preparation, 1 part by weight of the first preparation: 10 to 80 parts by weight of the second preparation, 1 part by weight of the first preparation: 20 to 60 parts by weight of the second preparation, or 1 part by weight of the first preparation: 30 to 40 parts by weight of the second preparation.

[0042] In the present invention, when the first formulation and the second formulation are each formulated separately, the first formulation can be administered intravenously once to five times a week, specifically once a week, twice a week, three times a week, four times a week, or five times a week, and more specifically, can be administered intravenously three times a week.

[0043] Additionally, the first formulation may be administered intravenously for one to three weeks, specifically for one week, two weeks or three weeks, and more specifically for two weeks.

[0044] In the present invention, when the first preparation and the second preparation are each formulated separately, the second preparation can be administered intravenously once a day.

[0045] Additionally, the second formulation may be administered intravenously for 1 to 5 days, specifically for 1, 2, 3, 4 or 5 days, and more specifically for 5 days.

[0046] The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined based on factors including the type and severity of the patient's disease, drug activity and sensitivity to the drug, administration time, administration route and excretion rate, treatment period, concurrent medications, and other factors well known in the medical field. It is important to take all of the above factors into consideration and administer an amount that achieves the maximum effect with the minimum amount without causing side effects, and this can be easily determined by those skilled in the art.

[0047] In the present invention, when the first preparation and the second preparation are each formulated separately, the first preparation may be formulated as an injection.

[0048] Additionally, the injection may contain a pH adjusting agent; an isotonic agent; and a surfactant.

[0049] Specifically, the pH adjusting agent serves to maintain the pH of the formulation without changing the pH of the formulation so that the peptide is stabilized. The pH adjusting agent may include any other pharmaceutically acceptable pH adjusting agent known in the art, including phosphate, histidine / histidine hydrochloride, sodium citrate / citric acid buffer, and mixtures of these pH adjusting agents may also be used. In addition, the concentration may be 1 mM to 50 mM, 1 mM to 30 mM, 1 mM to 20 mM, or 5 mM to 15 mM. In addition, the pH of the buffer solution may be specifically 5.0 to 7.0, and more specifically 5.5 to 6.5.

[0050] The above isotonic agent plays a role in maintaining an appropriate osmotic pressure when administering the peptide in the body, and also exhibits the effect of further stabilizing the peptide in the formulation. Examples of isotonic agents include sugar alcohols, water-soluble inorganic salts, amino acids, etc., and specifically, sodium chloride, which is a water-soluble inorganic salt, can be mentioned. In addition, the above isotonic agent can be contained in an amount of 0.1 to 2 w / v% with respect to the total injection, specifically, 0.1 to 1 w / v%, and more specifically, 0.5 to 1 w / v%.

[0051] The surfactant lowers the surface tension of the protein solution, thereby preventing the protein from adsorbing or aggregating on the hydrophobic surface. Examples of the surfactant include polysorbate 20 or polysorbate 80. In addition, the surfactant may be contained in an amount of 0.001 to 0.1 w / v% relative to the total injection, specifically 0.005 to 0.1 w / v%, and more specifically 0.005 to 0.05 w / v%.

[0052] In the present invention, the demyelinating disease is Charcot-Marie-Tooth disease (CMT), Chronic inflammatory demyelinating polyneuropathy (CIDP), Idiopathic inflammatory demyelinating disease, Hereditary neuropathy, Anti-MAG peripheral neuropathy, Progressive inflammatory neuropathy, Optic neuropathy, Devic's disease, Central pontine myelinolysis (CPM), Extrapontine Myelinolysis (EPM), Tabes dorsalis, Leukoencephalopathies, Demyelinating These may include, but are not limited to, demyelinating leukodystrophy, neuromyelitis optica, demyelinating optic neuritis, acute disseminated demyelination, periaxial encephalitis, central demyelination of corpus callosum, acute transverse myelitis, subacute necrotizing myelitis, or concentric sclerosis.

[0053] In the present invention, the composition can prevent or treat the demyelinating disease by improving motor nerve and sensory nerve damage, specifically motor nerve and sensory nerve damage due to demyelination.

[0054] In addition, the composition can prevent or treat demyelinating diseases by improving motor nerve conduction and sensory nerve conduction reduction, specifically, motor nerve conduction and sensory nerve conduction reduction caused by demyelination.

[0055] In a specific embodiment of the present invention, the inventors synthesized a trimer-type peptide using a PSP fragment (PSP monomer) and prepared an injectable formulation KINE-101 containing the peptide.

[0056] In addition, the inventors of the present invention confirmed that a synergistic effect on improving motor and sensory nerve damage was observed by intravenously administering KINE-101 in combination with intravenous immunoglobulin (IVIg) in a rat model of chronic inflammatory demyelinating polyneuropathy (CIDP).

[0057] Therefore, the inventors of the present invention confirmed the effect of improving motor and sensory nerve damage by intravenous combined administration of the peptide and IVIg in a demyelinating disease model, and therefore, the peptide and IVIg of the present invention can be usefully used in combination therapy for treating demyelinating diseases.

[0058] Hereinafter, the present invention will be described in detail by examples.

[0059] However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited to the following examples.

[0060] <Example 1> Preparation of KINE-101

[0061] Using PSP fragments (PSP monomers), trimer-type polymers were prepared as shown in [Table 1] below. Subsequently, the synthesized peptides were purified using high-performance liquid chromatography (Shimadzu Prominence HPLC), and the column used was Shiseido Capcell pak C18 Column (4.6 x 50 mm). In addition, the mass of the synthesized peptides was confirmed using a mass spectrometer (AXIMA Assurance, MALDI-TOF, Shimadzu).

[0062] Amino acid sequence molecular weight (MW) peptide PSPPSPPSP (SEQ ID NO: 1) 861.9 g / mol

[0063] Next, an injectable formulation (hereinafter referred to as 'KINE-101') containing the acetate salt of the synthesized peptide, 10 mM pH 6.0 phosphate buffer (PB), 0.8% sodium chloride (NaCl), and 0.01% polysorbate 20 was prepared.

[0064] <Example 2> Evaluation of the efficacy of KINE-101 and intravenous immunoglobulin (IVIg) in a rat model of chronic inflammatory demyelinating polyneuropathy (CIDP).

[0065] <2-1> Creation of CIDP rat model and drug administration

[0066] In order to investigate the effects of KINE-101 and intravenous immunoglobulin (IVIg) in demyelinating diseases, a c-EAN (chronic Experimental Autoimmune Neuritis) rat model, an animal model of chronic inflammatory demyelinating polyneuropathy (CIDP), a form of demyelinating disease, was created as follows, and KINE-101 and / or IVIg of <Example 1> were administered.

[0067] Specifically, as shown in the schematic diagram of Fig. 1, 7-week-old male Lewis rats were supplied, and after a 1-week acclimatization period, Solution A, in which peripheral myelin P0 protein (180-199) was dissolved in saline at 2 mg / mL, and Solution B, in which Mycobacterium tuberculosis was dissolved in Freund's incomplete adjuvant at 5 mg / mL, were prepared. After inserting a sterilized 25 mL tube into an icebox, Solution A and Solution B were mixed in a 1:1 ratio and homogenized using a homogenizer for 15 minutes to prepare an emulsion. The prepared emulsion was placed in a 1 mL syringe, the syringe was changed to 25 G, and stored in an icebox containing ice until use. Lewis rats were induced to become ill by subcutaneously (SC) injecting 200 μl of the emulsion into the base of the tail. Since body weight decreases depending on the severity of CIDP, the rats were divided into eight groups as shown in [Table 2] below, and the groups were separated after matching the average body weight of the induction group as much as possible. From the day after induction of the disease, KINE-101 dissolved in DPBS was administered intravenously (IV) three times a week at 6.25, 12.5, 25, and 37.5 mg / kg each, and / or IVIg was administered intravenously (IV) once a day at 400 mg / kg each for a total of five times.

[0068] Group Composition Measurement Number of Subjects G0WT control 3G1Vehicle control 8G2KINE-101 6.25mg / kg 8G3KINE-101 12.5mg / kg 8G4KINE-101 25mg / kg 8G5KINE-101 37.5mg / kg 7G6IVIG 400mg / kg 7G7IVIG 400mg / kg+KINE-101 12.5mg / kg 8Total Number 57

[0069] <2-2> Confirmation of the neurological damage improvement effect of KINE-101 and IVIg in a CIDP rat model

[0070] To investigate the effect of KINE-101 and IVIg on improving peripheral nerve damage in demyelinating diseases, nerve conduction studies (NCS) were performed using electrophysiological tests after administration of KINE-101 and / or IVIg to CIDP rat models.

[0071] Specifically, KINE-101 and / or IVIg were administered by the method described in Example <2-1>, and on the 14th and 15th days after disease induction, the mice were anesthetized with 1.5% isoflurane and then nerve conduction tests were performed on the left and right lower extremities. The fur was removed from the distal to the upper part of the lower extremities, and a Nicolet VikingQuest device was used as an electrophysiological test device to perform nerve conduction tests to measure motor and sensory nerves, respectively. For the nerve conduction tests, needle electrodes were placed on the motor or sensory nerves, the reference electrode was placed on the gastrocnemius muscle, and the stimulating cathode was placed close to the recording electrode in the middle of the posterior thigh to stimulate the distal and proximal parts, respectively. Motor nerve conduction velocity (MNCV) and compound muscle action potential (CMAP) of the motor nerves, and sensory nerve conduction velocity (SNCV) and sensory nerve action potential (SNAP) of the sensory nerves were measured to determine whether there was damage to the motor and sensory nerves.

[0072] As a result, as shown in Figure 2, the motor nerve conduction velocity was 60.8±1.3 m / s on average for the normal control group (G0), while the average value for the disease-induced group (G1) was 44.5±8.2 m / s, showing a statistically significant difference (p < 0.001).

[0073] The motor nerve conduction velocity measurements according to KINE-101 treatment were 53.0±10.6m / s (p = 0.017) in the 6.25mg / kg administration group (G2), 56.7±4.5m / s (p < 0.001) in the 12.5mg / kg administration group (G3), 54.9±3.6m / s (p < 0.001) in the 25mg / kg administration group (G4), and 53.1±9.0m / s (p = 0.011) in the 37.5mg / kg administration group (G5), showing statistically significantly improved results in all four groups compared to the disease-induced group (G1). In particular, the KINE-101 12.5 mg / kg administration group (G3) showed the greatest improvement among the four groups, showing a higher value than the IVIg 400 mg / kg administration group (G6) at 54.5 ± 11.9 m / s (p = 0.012).

[0074] In addition, when IVIg and KINE-101 12.5 mg / kg were co-administered (G7), better results were confirmed than when each drug was administered alone (57.4±10.5 m / s, p < 0.001).

[0075] In addition, as shown in Figure 3, the compound muscle action potential was measured to be 26.4±5.7 mV on average in the disease-induced group (G1), which was significantly lower than that in the normal control group (G0, 37.5±3.8 mV) (p < 0.001).

[0076] Compound muscle action potentials showed improved effects in all dose groups examined when KINE-101 was administered. In particular, statistically significant increases were observed in the 12.5 mg / kg group (G3, 33.2 ± 8.0 mV, p = 0.007) and the 25 mg / kg group (G4, 32.4 ± 7.3 mV, p = 0.011). The highest value observed in the 12.5 mg / kg group (G3) was higher than that of the IVIg 400 mg / kg group (G6), at 31.8 ± 9.1 mV.

[0077] When IVIg and KINE-101 12.5 mg / kg were co-administered (G7), the value was further improved compared to when each was administered separately, and the result was 35.2±11.4 mV (p = 0.008), which was closer to the normal control group (G0).

[0078] In addition, as shown in Figure 4, the sensory nerve conduction velocity was 22.7±2.9 m / s in the disease-induced group (G1), confirming that the sensory nerves were damaged compared to the normal control group (G0, 31.3±2.2 m / s) (p = 0.001).

[0079] The sensory nerve conduction velocity in the KINE-101-administered group was observed to be higher in all dose groups than in the disease-induced group (G1). Among these, the measurements in the 12.5 mg / kg administration group (G3, 27.5±3.3 m / s, p = 0.008) and 25 mg / kg administration group (G4, 26.9±4.3 m / s, p = 0.037) showed statistical significance.

[0080] This significant improvement in sensory nerve conduction velocity was similar to or slightly higher than the measured value (26.7±3.3 m / s, p = 0.028) of the IVIg monotherapy group (G6), and was also confirmed in the IVIg and KINE-101 combination therapy group (G7, 27.9±2.8 m / s, p = 0.003).

[0081] In addition, as shown in Fig. 5, the sensory nerve action potential measurement results showed that the average measurement value of the normal control group (G0) was 24.8±3.4uV, and the average measurement value of the disease-induced group (G1) was 13.9±5.6uV, which was confirmed to be significantly lower than that of the normal control group (G0).

[0082] In the KINE-101 administration group, sensory nerve action potentials were measured to have increased values ​​compared to the disease-induced group (G1) in all groups, and statistical significance was confirmed at 19.9±3.1uV (p = 0.018) in the 12.5mg / kg administration group (G3). Except for the 37.5mg / kg administration group (G5), the difference between the groups administered KINE-101 was not significant, but among them, the 12.5mg / kg administration group had the highest measured value, and the value was similar to the measurement result of the IVIg administration group (G6) (20.0±4.8uV, p = 0.042).

[0083] The measured values ​​in the IVIg and KINE-101 combination group (G7, 20.7±7.3uV, p = 0.041) were observed to be slightly higher than those in the single-administration group.

[0084] The above results show that compared to the normal control group, the disease-induced group showed significantly decreased motor nerve conduction velocity (MNCV), compound muscle action potential (CMAP), sensory nerve conduction velocity (SNCV), and sensory nerve action potential (SNAP) in the motor and sensory nerve conduction tests, indicating that a model representing the electrophysiological characteristics of CIDP was well-created. In addition, overall, the results of comparing the administered doses in all electrophysiological tests showed that the administration of 12.5 mg / kg of KINE-101 showed the highest improvement effect, and even higher values ​​were measured when IVIg and KINE-101 were co-administered, indicating a synergistic effect between the two drugs.

[0085] In the present invention, it was confirmed that a synergistic effect was exhibited in improving motor and sensory nerve damage by co-administering the peptide according to the present invention and intravenous immunoglobulin (IVIg) in a rat model of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Therefore, the peptide and IVIg can be usefully used in combination therapy for treating demyelinating diseases.

Claims

1. A pharmaceutical composition for preventing or treating demyelinating diseases, comprising as active ingredients a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin (IVIg).

2. A pharmaceutical composition for preventing or treating demyelinating disease, wherein the N- or C-terminus of the peptide in paragraph 1 is bonded to a protecting group selected from the group consisting of an acetyl group, a fluorenyl methoxy carbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, and polyethylene glycol (PEG).

3. A pharmaceutical composition according to claim 1, wherein the salt is an acetate salt.

4. A pharmaceutical composition according to claim 1, wherein the first preparation and the second preparation are administered intravenously.

5. A pharmaceutical composition according to claim 1, wherein the first preparation and the second preparation are administered individually, simultaneously, sequentially, or in a time-separated manner.

6. A pharmaceutical composition comprising a first preparation comprising a peptide composed of an amino acid represented by the sequence number 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin, wherein the first preparation is administered intravenously in an amount of 1 part by weight: 5 to 100 parts by weight of the second preparation.

7. A pharmaceutical composition according to claim 1, wherein the first preparation is administered intravenously once to five times a week.

8. A pharmaceutical composition according to claim 7, wherein the first formulation is administered intravenously for 1 to 3 weeks.

9. A pharmaceutical composition according to claim 1, wherein the second agent is administered intravenously once a day.

10. A pharmaceutical composition according to claim 9, wherein the second agent is administered intravenously for 1 to 5 days.

11. A pharmaceutical composition according to claim 1, wherein the first agent is formulated as an injection.

12. A pharmaceutical composition according to claim 11, wherein the injection agent contains a pH adjusting agent; an isotonic agent; and a surfactant.

13. A pharmaceutical composition according to claim 12, wherein the pH adjusting agent is a phosphate, histidine, and citric acid buffer solution.

14. A pharmaceutical composition according to claim 13, wherein the pH range of the buffer solution is 5.0 to 7.

0.

15. A pharmaceutical composition according to claim 12, wherein the tonicity agent is contained in an amount of 0.1 to 2 w / v% with respect to the total injection amount.

16. A pharmaceutical composition according to claim 12, wherein the isostatic agent is sodium chloride.

17. A pharmaceutical composition according to claim 12, wherein the surfactant is contained in an amount of 0.001 to 0.1 w / v% based on the total injection amount.

18. A pharmaceutical composition according to claim 12, wherein the surfactant is polysorbate 20 or polysorbate 80.

19. In paragraph 1, the demyelinating disease is Charcot-Marie-Tooth disease (CMT), Chronic inflammatory demyelinating polyneuropathy (CIDP), Idiopathic inflammatory demyelinating disease, Hereditary neuropathy, Anti-MAG peripheral neuropathy, Progressive inflammatory neuropathy, Optic neuropathy, Devic's disease, Central pontine myelinolysis (CPM), Extrapontine Myelinolysis (EPM), Tabes dorsalis, Leukoencephalopathies, Demyelinating A pharmaceutical composition selected from the group consisting of demyelinating leukodystrophy, neuromyelitis optica, demyelinating optic neuritis, acute disseminated demyelination, periaxial encephalitis, central demyelination of corpus callosum, acute transverse myelitis, subacute necrotizing myelitis, and concentric sclerosis.

20. A pharmaceutical composition according to claim 1, wherein the composition improves motor nerve and sensory nerve damage.

21. A pharmaceutical composition according to claim 1, wherein the composition improves reduction in motor nerve conduction and sensory nerve conduction.

22. A complex, mixed or combined preparation kit for preventing or treating demyelinating diseases, comprising a preparation comprising a peptide consisting of an amino acid represented by sequence number 1 or a pharmaceutically acceptable salt thereof; and a preparation comprising intravenous immunoglobulin.

23. A method for preventing or treating demyelinating disease, comprising administering to a subject a pharmaceutically effective amount of a first preparation comprising a peptide consisting of an amino acid represented by sequence number 1 or a pharmaceutically acceptable salt thereof; and a second preparation comprising intravenous immunoglobulin.

24. Use of a complex, mixed or combined preparation comprising a first preparation comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition for preventing or treating demyelinating diseases; and a second preparation comprising intravenous immunoglobulin as active ingredients.

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