JP2012092147A - Therapeutic agent for behcet's disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new medicine useful for treatment or prevention of Behcet's disease.SOLUTION: There are provided: a therapeutic agent composed of an anti-human TNF-α monoclonal antibody or its fragment as an active ingredient and effective for treating omentum uveitis in human individuals affected by Behcet's disease; and a prophylactic agent composed of an anti-human TNF-α monoclonal antibody or its fragment as an active ingredient and effective for preventing eye symptoms associated with retina uveitis in human individuals affected by Behcet's disease.

Description

  The present invention relates to a novel therapeutic agent or preventive agent for Behcet's disease. More specifically, the present invention relates to a therapeutic or prophylactic agent for uveitis in patients suffering from Behcet's disease comprising an anti-human tumor necrosis factor α (TNF-α) antibody as an active ingredient.

  Behcet's disease is an inflammatory disease of unknown cause that is invasive to multiple organs, (1) recurrent aphthous ulcers of the oral mucosa, (2) skin symptoms such as nodular erythema and hair follicle-like eruption, (3) eyes The main symptoms are 4 symptoms of uveitis and (4) vulva ulcer.

  Among the symptoms of Behcet's disease, ocular lesions due to uveitis (especially retinal uveitis) affect visual acuity and, in some cases, cause severe dysfunction leading to blindness. Inflammation of uveitis is characterized by repeated acute inflammation (eye attacks). Among the uveitis, those that mainly have inflammation in the front are called iridocyclitis (or iritis), and those that mainly have lesions in the fundus are called retinal uveitis (or retina choroiditis) (non-patent document). 1).

  As a treatment for the ocular symptoms of Behcet's disease, therapeutic agents such as colchicine and cyclosporine are usually used, and a combination therapy of these is sometimes used. In addition, systemic steroid therapy may be used for a short period of time in an eye attack of strong retinal uveitis (Non-patent Document 2).

  Colchicine is a kind of alkaloid and an immunosuppressant in a broad sense. Cyclosporine is an immunosuppressant that specifically acts on T lymphocytes. Cyclosporine has been shown to be effective against eye attacks in a double-blind study with colchicine as a control (Non-patent Document 3) and is widely used for the control of eye attacks.

  However, even with these various treatments, there were many cases in which eye attacks continued and eventually blinded. For this reason, a better therapeutic agent for suppressing ocular symptoms in Behcet's disease has been desired.

  On the other hand, cytokines such as TNF-α, IL-1, and IL-6 are known to be involved in various inflammatory diseases. Among them, it has been clarified that TNF-α regulates the production of cytokines such as IL-1 and IL-6 upstream. In active patients such as chronic rheumatoid arthritis and Crohn's disease, which are intractable inflammatory diseases, increased production of TNF-α has been reported (Non-patent document 4; Non-patent document 5), and TNF-α activity and production have been reported. Treatment by suppression is considered.

  Regarding the relationship between Behcet's disease and TNF-α, the following is known. TNF-α production ability of peripheral blood monocytes and intraocular T-cells in patients with Behcet's disease with uveitis has been observed to be higher than that of healthy individuals, and in particular, the activity of ocular symptoms It has been reported that the higher the TNF-α production ability of peripheral blood monocytes, the higher the patient (Non-patent Document 6).

  In addition, in an animal model of rat experimental autoimmune uveitis (EAU), TNF-α is considered to be a factor that exacerbates uveitis (Non-patent Document 7). It has been reported that anti-TNF-α polyclonal antibody (rabbit antiserum) was administered to mice and rats that induced this experimental autoimmune uveitis (EAU), and as a result, inflammation was suppressed. (Non-patent document 8; Non-patent document 9). However, administration at the early stage of immunization (afferant stage) was effective, but no effect was observed at the later stage of immunization (efferant stage). In addition, this pathological model induced experimental autoimmune uveorenitis (EAU) by immunizing mice or rats with photoreceptor retinoid binding protein (IRBP) or peptides derived therefrom. However, it is not a pathological model of Behcet's disease.

  Infliximab (cA2, also referred to as investigational drug TA-650) is a chimeric anti-TNF-α monoclonal antibody, an antigen-binding variable region derived from a mouse having high affinity for human TNF-α, It consists of the constant region of human IgG1. Infliximab has been confirmed in basic tests to have high selective binding to human TNF-α and neutralizing action against cell damage by TNF-α.

  Infliximab is very specific for human TNF-α, and only chimpanzee TNF-α is cross-reactive with non-human animal species TNF-α. Therefore, animal species that can evaluate the action of infliximab are limited to chimpanzees other than humans. Phase II clinical trials of infliximab have been conducted for rheumatoid arthritis, Crohn's disease, etc., and symptom-improving effects have been observed (Non-patent document 10; Non-patent document 11; Non-patent document 12; Non-patent document) 13; Non-patent document 14).

History of Medicine, 164, 13-16, 1993 The History of Medicine, 164, 77-80, 1993 Masuda et al., Clinical Evaluation, Vol.14, No.2, 437-461, 1986 Chu et al., Arthritis Rheum., 34, 1125-1132, 1991 Braegger et al., Lancet, 339, 89-91, 1992 Nakamura et al., Journal of the Japanese Ophthalmological Society, Vol. 96, No. 10, pp. 1282-1285, 1992 Nakamura et al., Investigative Ophthalmology & Visual Science, Vol.35, No.11, p.3884-3889, 1994 Sartani et al., Investigative Ophthalmology & Visual Science, Vol. 37, No. 11, 221-2218, 1996 Nakamura et al., Journal of the Japanese Ophthalmological Society, Vol. 101, No. 12, 975-986, 1997 Elliot et al., Arthritis Rheum. 36, 1681-1690, 1993 Elliot et al., Lancet, 344, 1125-1127, 1994 Elliot et al., Lancet, 344, 1105-1110, 1994 Dekx et al., Lancet, 342, 173-174, 1993 Hendrik et al., Gastroenterology, 109, 129-135, 1995

  An object of the present invention is to provide a new drug useful for the treatment and prevention of Behcet's disease.

  The present inventor found that the anti-TNF-α antibody can be suitably used for improving ocular symptoms in Behcet's disease having uveitis (retinal uveitis), and completed the present invention.

That is, the present invention
[1] a therapeutic agent for retinal uveitis in a human individual suffering from Behcet's disease comprising an anti-human TNF-α monoclonal antibody or a part thereof as an active ingredient; and [2] anti-human TNF- The present invention relates to a prophylactic agent for preventing ocular symptoms associated with retinal uveitis in a human individual suffering from Behcet's disease, comprising an α monoclonal antibody or a part thereof as an active ingredient.

  The present invention provides a therapeutic agent and a preventive agent useful for uveitis in Behcet's disease.

  The therapeutic agent or preventive agent of the present invention is effective for treating or preventing Behcet's disease having uveitis in an individual. It can also be applied to the treatment of uveitis due to Behcet's disease. Such uveitis includes retinal uveitis and iridocyclitis. The therapeutic agent or preventive agent of the present invention can be particularly suitably applied to retinal uveitis (particularly retinal uveitis having an active lesion in the fundus).

  The active lesion refers to a lesion that repeats strong vitreous opacification in combination with fundus inflammation (or fundus lesion) accompanied by bleeding, edema, exudation spots, and the like. Such active lesions may be accompanied by optic neuritis, anterior chamber purulent iritis, and ciliary body inflammation.

  The therapeutic agent or prophylactic agent of the present invention suppresses or prevents various ocular symptoms associated with uveitis caused by Behcet's disease. Among such eye symptoms, eye seizures can be mentioned as the main one. In addition, eye symptoms include decreased visual acuity, anterior ocular inflammation, vitreous opacification, and fundus inflammation.

  Examples of the type of eye attack include a fundus type, an anterior segment type, and a pan uveal type. Of these, the fundus oculi type and the pan uvea type are serious, but the therapeutic agent of the present invention suitably exerts an inhibitory effect also on these.

  Moreover, the therapeutic agent of this invention exhibits an effect suitably also to the uveitis in which an effect is not acquired by administration of a cyclosporin, and the ocular symptom accompanying it.

  In the present specification, treatment includes improvement of symptoms, prevention of severity, maintenance of remission, prevention of relapse, and prevention of recurrence. Prevention in the preventive agent of the present invention refers to prevention of the development of uveitis and the accompanying ocular symptoms, and the therapeutic agent of the present invention is applied. Including prevention of the onset of various symptoms as described above.

  The therapeutic agent or prophylactic agent of the present invention can be suitably administered parenterally, for example, by intravenous injection such as infusion. In addition, it can be administered systemically or locally by intramuscular injection, subcutaneous injection, or the like. Further, it may be administered as an eye drop locally.

  The therapeutic agent of the present invention is administered in an amount sufficient to cure or at least partially block disease symptoms. In addition, the preventive agent of the present invention is administered in an amount sufficient to prevent such disease symptoms. The dosage as an active ingredient anti-TNF-α antibody varies depending on the administration method, patient age, weight, condition and disease to be treated or prevented, but the daily dosage for an adult is usually About 0.01-100 mg / kg. In the case of intravenous administration, the dose is usually 2.5 to 20 mg / kg, preferably 3.0 to 10 mg / kg. In the case of subcutaneous, intramuscular or intraocular topical administration, it is usually administered at a dose in the range of 0.1 to 2.5 mg / kg.

  The administration period can be appropriately selected depending on the age and symptoms of the patient. Subsequent doses can be administered at the same dose as the first or previous dose for the patient, or at a dose less than or greater. The second and subsequent administrations are preferably performed immediately before or during the recurrence stage of the disease or disease symptoms. A total of 2, 3, 4 or more doses can be administered to the patient as needed.

  The anti-TNF-α antibody may be administered as an individual therapeutic agent or prophylactic agent, or may be used in combination with other therapeutic agents or prophylactic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

  The dosage form of the preparation is used in a form corresponding to the administration method. The formulation can be formulated according to conventional methods, for example, as a solution, suspension, emulsion or lyophilized powder (Remington's Pharmaceutical Science, latest edition, Mark Publishing Company, Easton, USA).

  The preparation may contain both pharmaceutically acceptable carriers and additives.

  For example, when used as an injection, the purified antibody is dissolved in a solvent (for example, water, physiological saline, Ringer's solution, dextrose solution, glucose solution, etc.), and an adsorption inhibitor (for example, Tween 80, Tween 20, gelatin, human serum albumin, etc.) can be used. For example, injectable preparations are prepared by dissolving 1.5% by weight of active ingredient in 0.9% sodium chloride solution.

  It may be formulated as lyophilized so that it can be dissolved and reconstituted before use. As an excipient for lyophilization, for example, sugar alcohols and saccharides such as sucrose, mannitol, and glucose can be used.

  As the anti-human TNF-α antibody used in the therapeutic agent or prophylactic agent of the present invention, an antibody having a high affinity for TNF-α in the human body and neutralizing its activity is preferably used. Can be used.

The affinity for human TNF-α preferably has an Ka affinity of at least 10 ⁸ M ⁻¹ , more preferably at least 10 ⁹ M ⁻¹ . In addition, it has strong in vivo TNF-α blocking ability and / or neutralizing ability (for example, ability to neutralize cytotoxic activity of human TNF-α, ability to block TNF-induced IL-6 secretion, TNF-inducing ability) It is preferable to have the ability to block clotting promoting activity. Moreover, the thing with high specificity with respect to human TNF- (alpha) is preferable.

  As the anti-human TNF-α antibody used in the present invention, a monoclonal antibody having low immunogenicity and low toxicity (such as those having a low HAMA response and / or HACA response) or a part thereof can be used. Such antibodies include chimeric antibodies, humanized antibodies, human antibodies, primatized antibodies, resurfaced antibodies, single chain antibodies, and the like. “HAMA” indicates a human anti-murine antibody, and “HACA” indicates a human anti-chimeric antibody.

  As used herein, “low” immunogenicity means that less than about 75%, preferably less than about 50% of patients treated with a significant HACA or HAMA response and / or treatment Defined as producing a low titer (less than about 300, preferably less than about 100 when measured by a double antigen enzyme immunoassay) (reference: Elliott et al., Lancet, 344, 1125). ~ 1127, 1994).

  A chimeric antibody is an immunoglobulin molecule characterized by the joining of two or more parts from different animal species. In general, the variable region of a chimeric antibody is derived from a non-human mammalian antibody (eg, a mouse monoclonal antibody), and the immunoglobulin constant region is derived from a human immunoglobulin molecule. Preferably, a variable region with low immunogenicity is selected and combined with a human constant region that also has low immunogenicity. And it is preferable that the combination also has low immunogenicity. Chimeric antibodies include monovalent, divalent or multivalent immunoglobulins. A monovalent chimeric antibody is a dimer (HL) formed by a chimeric H chain linked to a chimeric L chain via a disulfide bridge. A bivalent chimeric antibody is a tetramer (H2L2) formed by two HL dimers linked via at least one disulfide bridge.

  Chimeric antibodies and methods for their production have already been described in the art (Morrison et al., Proc. Natl. Acad. Sci. USA 81: 6851-6855 (1984); Boulianne et al., Nature 312: 643-646. (1984); Neuberger et al., Nature 314: 268-270 (1985); Taniguchi et al., European Patent Application No. 171496 (published 19 February 1985); Morrison et al., European Patent Application No. 173494 ( Published on March 5, 1986); Neuberger et al., International Publication No. 86/01533 pamphlet (published on March 13, 1986); Kudo et al., European Patent Application No. 184187 published on June 11, 1986) Morrison et al., European Patent Application No. 173494 (published March 5, 1986); Sahagan et al., J. Immunol. 137: 1066-1074 (1986); Robinson et al., WO 87/02671 ( Liu et al., Proc. Natl. Acad. Sci. USA 84: 3439-3443 (1987); Sun et al., Proc. Natl. Acad. Sci. USA, 84: 214-218 (1987) ); Better et al., Science 240: 1041 1043 (1988); and Harlow and Lane, ANTIBODIES: ALABORATORY MANUAL Cold Spring Harbor Laboratory (1988)).

  Antibody humanization and surface reprocessing can further reduce the immunogenicity of the antibody (Winter, US Pat. Nos. 5,225,539 and EP 239400; Padlan et al., EP 519596; Pedersen et al. EP 592106).

  In addition, human antibodies and methods for producing them have already been described in the art (Lonberg et al., Nature 368: 856-859 (1994); Kay et al., WO 92/03918 pamphlet (March 1992 Jakobovits et al., WO 91/10741 pamphlet (published July 25, 1991); Brenner et al., WO 96/33735 pamphlet (published October 31, 1996); Brenner et al. WO 96/34096 (published October 31, 1996); Green et al., WO 98/24893 pamphlet (published June 11, 1998); Burton et al., Adv. Immunol. 57: 191 ~ 280 (1994); Tsurushita et al., Gene 172: 59-63 (1996); Waterhouse et al., Nucl. Acids. Res. 21: 2265-2266 (1993)).

  A preferred specific example of the anti-human TNF-α antibody used in the therapeutic agent or prophylactic agent of the present invention is infliximab. Infliximab (generic name: Infliximab, trade name: Remicade, manufactured by Centocor Inc. (USA)) (also referred to as cA2 or investigational drug TA-650) is designated as mouse anti-human TNF-α mouse IgG1 antibody (monoclonal antibody A2). (Ii) an antigen-binding variable region and a constant region of human IgG1 kappa immunoglobulin.

  A method for producing infliximab (cA2) is described in JP-T-6-506120. Chimeric antibody cA2 is produced by a cell line designated c168A. c168A was deposited with the American Type Culture Collection (Rockville, Md.) as a “determined culture deposit”. Mouse IgG1 monoclonal antibody A2 is also produced by a cell line designated c134A.

  The anti-human TNF-α antibody used in the therapeutic agent or prophylactic agent of the present invention includes an antibody that binds to the same epitope as that in human TNF-α recognized by infliximab (cA2) (that is, human TNF-of infliximab) An antibody that competitively blocks binding to α) is also expected to have substantially the same effect as infliximab (cA2), and can be preferably used.

  Preferred methods for determining the specificity and affinity of mAbs by competitive inhibition have already been described in the art (Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY) 1988), Colligan et al., Current Protocols in Immunology, Greene Publishing Assoc. And Wiley Interscience, New York (1992, 1993), Kozbor et al., Immunol. Today 4: 72-79 (1983), Ausubel et al., Current Protocols in Molecular. Biology, Wiley Interscience, New York (1987, 1992, 1993); and Muller, Meth. Enzymol. 92: 589-601 (1983)).

  The term “epitope” means a portion of an antigen that is recognized by an antibody and capable of binding at one or more antigen binding regions of the antibody. Epitopes usually have chemically active surface groups of molecules such as amino acids and sugar side chains that have specific three-dimensional structural characteristics and specific charge characteristics.

  Generally, an epitope comprises at least about 5 (usually less than about 22) amino acid residues encompassing (or partially overlapping) at least one in the region.

  In addition to the above, suitable antibodies include (i) amino acid residues from about 87 to about 108, (ii) amino acids from about 59 to about 80 in human TNF-α, and ( iii) A substance that binds to one or more amino acids in an epitope present in a region selected from the group consisting of about 59th to about 80th amino acid residues and about 87th to about 108th amino acid residues Is mentioned. More specifically, the 87th to 108th amino acid residues; the 59th to 80th amino acid residues; or the 59th to 80th amino acid residues and the 87th to 108th amino acid residues And those that bind to one or more amino acids in the epitope present in the region. Such suitable antibodies bind to at least one, preferably about 5 or more amino acids in these regions. Such an antibody production method is also described in JP-A-6-506120. Such an antibody is expected to be substantially as effective as infliximab (cA2). Moreover, Eck and Sprang (J. Biol. Chem. 264 (29): 17595-17605 (1989)) showed the putative receptor binding center (11th-13th in human TNF-alpha, 37-42th, 49 Without binding to the 57th and 155th to 157th amino acid residues), the action of TNF-α is blocked.

  As an antibody used for the therapeutic agent or prophylactic agent of the present invention, the whole antibody may be used, or a fragment or partial region thereof may be used. Fragments include, for example, Fab, Fab ′, F (ab ′) 2 and Fv. These fragments lack the Fc fragment of the complete antibody, disappear more rapidly from the circulatory system, and may have lower nonspecific tissue binding than the complete antibody (Wahl et al., J. Nucl. Med. 24: 316-325 (1983)). These fragments can be completely purified by proteolytic cleavage with enzymes such as papain (production of Fab fragments) and pepsin (production of F (ab ') 2 fragments) using methods well known in the art. Produced from antibodies.

  The present invention will be described in more detail based on examples, but the present invention is not limited to such examples.

Example 1 Evaluation Method for Effectiveness in Behcet's Disease Patients The effect on Behcet's disease patients with uveitis (retinal uveitis) is tested as follows.

(1) Target patients The subjects are Behcet's disease patients with retinal uveitis with active lesions in the fundus. Here, the active lesion means a lesion that repeats strong vitreous opacification in combination with fundus inflammation (or fundus lesion) accompanied by bleeding, edema, exudation spots and the like. Such active lesions may be accompanied by optic neuritis, anterior chamber purulent iritis, and ciliary body inflammation.

(2) Period of pre-dose observation and evaluation Before observation, take an observation period of approximately 6 to 10 weeks. In addition, the observation period is approximately 8 to 14 weeks before the observation period, and observation is performed according to the observation period. After the observation period, the first administration is performed 2-3 weeks later, and the efficacy is evaluated from the first administration day to 12-14 weeks.

(3) Drug used in the test Drug name: Infliximab (also referred to as TA-650)
Dosage form: injection (lyophilized product containing 100 mg of anti-TNF-α chimeric monoclonal antibody in one vial)
Preparation of drug solution: 9.6 mL of water for injection is poured into a vial containing 100 mg of lyophilized powder of infliximab (volume: 20 ml) and the vial is carefully rotated to completely dissolve the lyophilized powder. Thus, a colorless to pale yellow solution containing 10 mg of anti-TNF-α chimeric monoclonal antibody in 10 mL is prepared. The solution is prepared at the time of use.

(4) Dosage and dose Infliximab is dosed at either 5 mg / kg or 10 mg / kg. For the first administration (week 0), dosing is started by selecting the remission period (when the disappearance (disappearance) of inflammation was confirmed by ophthalmic examination), and the same dose is given at weeks 0, 2, 6 and 10 as follows: Intravenously infuse.

  That is, after measuring the necessary amount of the drug solution converted from the patient's body weight (prepared in (3) above) with a syringe and injecting it into a physiological saline solution for infusion, Intravenously in about 2 hours.

  Body temperature, blood pressure, and pulse rate are measured every 30 minutes before administration, during administration, and 2 hours after the end of administration to confirm that there is no abnormality in the patient's condition.

(5) Efficacy Evaluation Method It is known that Behcet's disease patients with retinal uveitis cause irreversible loss of visual acuity by repeating eye attacks. Therefore, the frequency of eye attacks is examined as a main evaluation item for efficacy. Examination and observation of visual acuity (remission period), ocular findings, and extraocular symptoms as secondary evaluation items for efficacy. Ocular seizures, visual acuity, and ocular findings are examined and observed for both eyes every 1 to several weeks during the retroactive period, every 2 weeks during the observation period, every day of the first administration, and every 2 weeks during the efficacy evaluation period. If there is a subjective symptom of an eye attack, examine and observe within one week from that date if possible.

  As for extraocular symptoms, look back at the initial administration day (week 0) and weeks 2, 6, 10, and 14 of the efficacy evaluation period for 4 weeks before (but 2 weeks before administration for 2 weeks before administration). Observe.

<Frequency of eye attacks>
If an ophthalmic examination confirms anterior ocular inflammation (flare, cell count), vitreous opacification, or ocular fundus inflammation (edema, exudation, bleeding, vascular whitening), it is evaluated as “having an eye attack” The

  In addition, if an eye attack is observed, the state of the eye attack (new or continued), the degree of the eye attack (mild, moderate or advanced) and the type of eye attack (anterior segment type, fundus type, vitreous type) Or pan-vulnerable membrane type).

<Ocular findings>
For anterior segment findings, a slit lamp microscope (Haag-Streit or equivalent slit lamp microscope) is used to observe the number of cells in the anterior chamber and the flare (turbidity) in the anterior chamber. A slit lamp microscope observes one field of view with maximum light intensity, slit width of 0.5 mm, and slit height of 8 mm.

  Vitreous findings are observed for the degree of vitreous opacity. Fundus findings are observed for inflammation of the fundus (edema, exudation, bleeding, vascular whitening).

  The observation result is determined according to the following criteria.

Anterior segment findings / cell count in the anterior chamber:
0: 0-4 (none, nil)
1: 5-10 (mild)
2: 11-20 pieces (moderate, moderate)
3: 21-50 pieces (marked)
4: 51 or more (severe, severe)
5: Hypopyon

Anterior segment findings / Anterior chamber flare:
0: None (none, nil)
1: A slight turbidity is recognized (mild)
2: Obvious clear turbidity (moderate, moderate)
3: Strong turbidity is recognized (marked)
4: Strong turbidity with fibrin (severe, severe)

Vitreous findings:
0: Looks exactly like normal eyes (none, nil)
1: The posterior pole is clearly visible, but there is some turbidity when focused in the vitreous body (minimum, minimal)
2: The details of the back pole can be understood, but the appearance is slightly blurred (mild, mild)
3: Details of the back pole appear faint (moderate, moderate)
4: The details of the back pole are barely visible (significant, marked)
5: The details of the back pole are not visible at all (severe, severe)

Fundus findings:
0: No symptoms (none, nil)
1: Mild (mild)
2: Moderate (moderate)
3: Remarkable (significant, marked)

  Other findings include intraocular pressure, eye movement (normal / abnormal), and corneal deposits, post-iris adhesion, peripheral pre-iris adhesion, iris rubeosis, and retinal detachment.

<Sight (remission period)>
Measure only for eyes that have had eye attacks during the retroactive, observation, or efficacy evaluation period. Further, when the visual acuity measurement at 14 weeks after administration is not in remission, visual acuity is measured at the time when the first remission is reached up to 26 weeks after administration. Here, “remission period” means when inflammation disappears (disappears) by ophthalmic examination.

<Extraocular symptoms>
As extraocular symptoms, examine and observe the presence of oral after, genital ulcers and skin symptoms (nodular erythema, folliculitis-like rash, subcutaneous thrombophlebitis, etc.) caused by Behcet's disease.

Example 2 Evaluation Results of Efficacy in Behcet's Disease Patients Infliximab (5 mg / kg) according to the method described in Example 1 for 2 Behcet's disease patients with retinal uveitis (fundus uveitis) And the efficacy against ocular symptoms was evaluated.

  Both cases were patients with Behcet's disease with retino- uveitis with active lesions in the fundus, and multiple uveal or fundus-type eye attacks were observed multiple times during the observation period before drug administration. It was. In addition, all of them have a history of receiving cyclosporine in the past but having no effect on ocular symptoms.

  The evaluation results of effectiveness are shown in Tables 1 to 4. As shown in these tables, eye attacks were observed in the retrospective and observation period in the two cases (Case A and Case B). The number of new eye attacks during retrospective period to observation period of case A and case B was 4 times in total (3 times in retrospection period 8 weeks, 1 time in observation period 6 weeks) and 6 times in total (retroactivity period 10 weeks) 3 times during the observation period and 3 times during the 10 weeks). On the other hand, in all cases, no new eye seizures were observed during the evaluation period after infliximab administration, and no seizures continued.

  In all cases, ocular findings (anterior ocular findings, vitreous findings and fundus findings) tended to improve symptoms during the evaluation period compared to during the observation period.

  None of the adverse events such as side effects were observed during or after administration.

In addition, the following are mentioned as an aspect of this invention.
[1] A therapeutic agent for uveitis in an individual suffering from Behcet's disease, comprising an anti-human TNF-α antibody as an active ingredient.
[2] The therapeutic agent according to [1] above, wherein the uveitis is retinal uveitis.
[3] The therapeutic agent according to [1], wherein the uveitis is retinal uveitis having an active lesion on the fundus.
[4] The therapeutic agent according to the above [1], wherein the uveitis is accompanied by symptoms of an eye attack.
[5] The therapeutic agent according to the above [1], which is a therapeutic agent used for suppressing ocular symptoms associated with uveitis.
[6] The therapeutic agent according to [5] above, wherein the ocular symptom associated with uveitis is an eye attack.
[7] The therapeutic agent according to [5] above, wherein the ocular symptom associated with uveitis is a fundus-type or pan-uvial eye attack.
[8] The therapeutic agent according to [5] above, wherein the ocular symptom associated with uveitis is a symptom selected from decreased visual acuity, anterior ocular inflammation, vitreous opacification, and fundus inflammation.
[9] The therapeutic agent according to [5] above, wherein the ocular symptom associated with uveitis is an ocular symptom that cannot be suppressed by administration of cyclosporine.
[10] Any of the above [1] to [9], wherein the anti-human TNF-α antibody is a monoclonal antibody selected from the group consisting of a chimeric antibody, a humanized antibody and a human antibody, or an antibody thereof. Or a therapeutic agent according to any one of the above.
[11] The therapeutic agent according to any one of [1] to [10] above, wherein the anti-human TNF-α antibody is an antibody that binds to the same epitope as that in human TNF-α recognized by infliximab.
[12] An anti-human TNF-α antibody comprises (i) about 87th to about 108th amino acid residues, (ii) about 59th to about 80th amino acid residues in human TNF-α, and (Iii) binds to one or more amino acids in an epitope present in a region selected from the group consisting of amino acid residues from about 59 to about 80 and about 87 to 108 The therapeutic agent according to any one of [1] to [11], which is an antibody.
[13] The therapeutic agent according to any one of [1] to [10], wherein the anti-human TNF-α antibody is infliximab.
[14] The therapeutic agent according to any one of [1] to [13], which is a preparation for intravenous, subcutaneous, intramuscular or ocular topical administration.
[15] The therapeutic agent according to any one of [1] to [14] above, which is a preparation for intravenous administration at a dose in the range of 2.5 to 20 mg / kg.
[16] The therapeutic agent according to any one of the above [1] to [14], which is a preparation for subcutaneous, intramuscular or ocular topical administration at a dose in the range of 0.1 to 2.5 mg / kg.
[17] A prophylactic agent for preventing uveitis in an individual suffering from Behcet's disease, comprising an anti-human TNF-α antibody as an active ingredient.
[18] The prophylactic agent according to [17], wherein the uveitis is retinal uveitis.
[19] The prophylactic agent according to the above [17], which is a prophylactic agent used for the prevention of ocular symptoms associated with uveitis.
[20] The prophylactic agent according to the above [19], wherein the ocular symptom associated with uveitis is an eye attack.
[21] The prophylactic agent according to [19] above, wherein the ocular symptom associated with uveitis is a fundus-type or pan-uvial eye attack.
[22] The prophylactic agent according to [19] above, wherein the ocular symptom associated with uveitis is a symptom selected from decreased visual acuity, anterior ocular inflammation, vitreous opacification, and fundus inflammation.
[23] Any of [17] to [22] above, wherein the anti-human TNF-α antibody is a monoclonal antibody selected from the group consisting of a chimeric antibody, a humanized antibody and a human antibody, or an antibody comprising a part thereof. Or a preventive agent.
[24] The prophylactic agent according to any of [17] to [23] above, wherein the anti-human TNF-α antibody is an antibody that binds to the same epitope as that in human TNF-α recognized by infliximab.
[25] An anti-human TNF-α antibody comprises (i) amino acid residues from about 87 to about 108, (ii) amino acid residues from about 59 to about 80 in human TNF-α, and (Iii) binds to one or more amino acids in an epitope present in a region selected from the group consisting of amino acid residues from about 59 to about 80 and about 87 to 108 The prophylactic agent according to any one of [17] to [24], which is an antibody.
[26] The prophylactic agent according to any of [17] to [23] above, wherein the anti-human TNF-α antibody is infliximab.
[27] A method for treating or preventing uveitis in a patient with Behcet's disease, which comprises administering an effective dose of an anti-human TNF-α antibody to the patient.

Claims (23)

  A therapeutic agent for retinal uveitis in a human individual suffering from Behcet's disease comprising an anti-human TNF-α monoclonal antibody or a part thereof as an active ingredient.   The therapeutic agent according to claim 1, wherein the retinal uveitis is retinal uveitis having an active lesion on the fundus.   The therapeutic agent according to claim 1 or 2, wherein the retinal uveitis is accompanied by symptoms of an eye attack.   The therapeutic agent of Claim 3 which is a therapeutic agent used for suppression of the ocular symptom accompanying retinal uveitis.   The therapeutic agent according to claim 4, wherein the ocular symptom associated with retinal uveitis is an eye attack.   The therapeutic agent according to claim 4, wherein the ocular symptom associated with retinal uveitis is a fundus-type or pan-uvial eye attack.   The therapeutic agent according to claim 4, wherein the ocular symptom associated with retinal uveitis is a fundus type eye attack.   The therapeutic agent according to claim 4, wherein the ocular symptom associated with retinal uveitis is a symptom selected from decreased visual acuity, anterior ocular inflammation, vitreous opacification, and fundus inflammation.   The therapeutic agent according to claim 4, wherein the ocular symptom associated with retinal uveitis is an ocular symptom that cannot be suppressed by administration of cyclosporine.   The therapeutic agent according to any one of claims 1 to 9, wherein the anti-human TNF-α monoclonal antibody is a monoclonal antibody selected from the group consisting of a chimeric antibody, a humanized antibody and a human antibody.   The therapeutic agent according to any one of claims 1 to 10, wherein the anti-human TNF-α monoclonal antibody is an antibody that binds to the same epitope as that in human TNF-α recognized by infliximab.   The anti-human TNF-α monoclonal antibody comprises (i) amino acid residues from about 87 to about 108, (ii) amino acids from about 59 to about 80 in human TNF-α, and (iii) An antibody that binds to one or more amino acids in an epitope present in a region selected from the group consisting of amino acid residues from about 59 to about 80 and about 87 to 108; The therapeutic agent according to any one of claims 1 to 11.   The therapeutic agent according to any one of claims 1 to 12, which is a preparation for intravenous, subcutaneous, intramuscular or ocular topical administration.   The therapeutic agent according to any one of claims 1 to 12, which is a preparation for intravenous administration at a dose ranging from 2.5 to 20 mg / kg.   The therapeutic agent according to any one of claims 1 to 12, which is a preparation for subcutaneous, intramuscular or ocular topical administration at a dose in the range of 0.1 to 2.5 mg / kg.   A prophylactic agent for preventing ocular symptoms associated with retinal uveitis in a human individual suffering from Behcet's disease, comprising an anti-human TNF-α monoclonal antibody or a part thereof as an active ingredient.   The preventive agent according to claim 16, wherein the ocular symptom associated with retinal uveitis is an eye attack.   The prophylactic agent according to claim 16, wherein the ocular symptom associated with retinal uveitis is a fundus-type or pan-uvial eye attack.   The preventive agent according to claim 16, wherein the ocular symptom associated with retinal uveitis is a fundus type eye attack.   The preventive agent according to claim 16, wherein the ocular symptom associated with retinal uveitis is a symptom selected from decreased visual acuity, anterior ocular inflammation, vitreous opacification, and fundus inflammation.   The preventive agent according to any one of claims 16 to 20, wherein the anti-human TNF-α monoclonal antibody is a monoclonal antibody selected from the group consisting of a chimeric antibody, a humanized antibody and a human antibody.   The prophylactic agent according to any one of claims 16 to 21, wherein the anti-human TNF-α antibody is an antibody that binds to the same epitope as that in human TNF-α recognized by infliximab.   An anti-human TNF-α antibody comprising (i) about 87 to about 108 amino acid residues, (ii) about 59 to about 80 amino acid residues in human TNF-α, and (iii) An antibody that binds to one or more amino acids in an epitope present in a region selected from the group consisting of amino acid residues from about 59 to about 80 and about 87 to 108 The preventive agent according to any one of claims 16 to 22.