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(12) Patent Application Publication (10) Pub. No.: US 2010/0172909 A1 Nishibori Et Al

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US 20100172909A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0172909 A1 Nishibori et al. (43) Pub. Date: Jul. 8, 2010 (54) CEREBRAL EDEMA SUPPRESSANT (30) Foreign Application Priority Data (76) Inventors: Masahiro Nishibori, Okayama-shi Oct. 24, 2005 (JP) ................................. 2005-3O8949 (JP); Shuji Mori, Okayama-shi (JP); Hideo Takahashi, Okayama-shi (JP); Yasuko Publication Classification Tomono, Okayama-shi (JP): Naoto (51) Int. Cl. Adachi, Kyoto-shi (JP); Keyue Liu, A 6LX 39/395 (2006.01) Touon-shi (JP) A6IP 43/00 (2006.01) Correspondence Address: WENDEROTH, LIND & PONACK, L.L.P. (52) U.S. Cl. ..................................................... 424/139.1 1030 15th Street, N.W., Suite 400 East Washington, DC 20005-1503 (US) (21) Appl. No.: 12/634,790 (57) ABSTRACT (22) Filed: Jan. 4, 2010 The objective to be solved by the present invention is to provide a method for effectively suppressing cerebral edema. Related U.S. Application Data The method for Suppressing cerebral edema according to the (63) Continuation-in-part of application No. 12/084,044, present invention is characterized in comprising a step of filed on Apr. 24, 2008, now abandoned, filed as appli administering an anti-HMGB 1 antibody recognizing cation No. PCT/JP2006/320436 on Oct. 13, 2006. 208EEEDDDDE215 (SEQID NO: 1) as an HMGB1 epitope. 8:38-3::::::isis: 88 grogg A:::::::::38: 38t:3{xy 38:::::sier88 gro.3 Patent Application Publication Jul. 8, 2010 Sheet 1 of 4 US 2010/0172909 A1 es O O C wa o c O V v (D 92 s. ON- I - o its 5 wn a 9 - Yee v O Y O ea 5 O O NY O CC o S O . v se C 9E k sw O S O queto E C (C C (s ma 5 CC O "a S s CC eAoouou uo WWOJO unoue uOSsedx. Patent Application Publication Jul. 8, 2010 Sheet 2 of 4 US 2010/0172909 A1 Patent Application Publication US 2010/0172909 A1 (6u/6u) enq Suen jounoue e6exee Patent Application Publication Jul. 8, 2010 Sheet 4 of 4 US 2010/0172909 A1 (%)x. ...paleisulupe xx.... --> semigoNH Alio 8883 & O 8.8d. i03 essex e^. i.e. ifid exee joinoue at a de e. US 2010/0172909 A1 Jul. 8, 2010 CEREBRAL EDEMIA SUPPRESSANT 181. Concerning the anti-HMGB1 antibody, it is only experi mentally demonstrated that certain anti-HMGB1 antibody TECHNICAL FIELD inhibits cell migration of HMGB1, and it is not experimen 0001. The present invention relates to a drug for suppress tally demonstrated at all that the anti-HMGB1 antibody is ing cerebral edema. useful for Suppressing edema. Cerebral edema is not described in the publication either. BACKGROUND ART DISCLOSURE OF THE INVENTION 0002 Cerebral edema is a condition characterized by an excess of watery fluid collected in the extracellular spaces of 0007 Under the above circumstance, the objective to be the brain, such as circumferences of brain cell and cerebral solved by the present invention is to provide a method for blood vessel. Cerebral edema needs aggressive medical treat effectively suppressing cerebral edema. ment, since cerebral edema increases pressure in the brain to 0008. The present inventors have continuously studied cause death. anti-HMGB1 antibody. As a result, the present inventors 0003 Cerebral edema is classified into vasogenic edema found out that the anti-HMGB1 antibody which specifically and cytotoxic edema. Vasogenic edema is caused by break binds to C-tail of HMGB1 can effectively suppress cerebral down of blood-brainbarrier due to cerebral contusion, intrac edema, resulting in completion of the present invention. erebral hemorrhage, cerebral tumor and the like, and by 0009. The method for suppressing cerebral edema accord excessive increase of vascular permeability, which leads leak ing to the present invention is characterized in comprising a age and accumulation of plasma component outside of brain step of administering an anti-HMGB1 monoclonal antibody cell. Cytotoxic edema is caused by increasing fluid compo recognizing 208EEEDDDDE215 as an HMGB1 epitope. nent in brain cell due to hypoxia, impaired metabolism and 0010. According to the present invention method, cerebral the like. It is said that the breakdown of the blood-brain edema can be effectively suppressed. In addition, it is con barrier is not observed for the case of cytotoxic edema. How sidered that a possibility generating a serious adverse side ever, it is difficult to clearly distinguish cytotoxic edema from effect is extremely low based on the relatively safe clinical vasogenic edema, since disease condition may transit from application of antibody drugs currently used Therefore, the vasogenic edema to cytotoxic edema. Therefore, it is very method for suppressing cerebral edema according to the important for Suppressing cerebral edemato inhibit the break present invention is extremely useful. down of the blood-brain barrier, that is, excessive increase of vascular permeability. 0004 As the therapeutic agent for cerebral edema, glyc BRIEF DESCRIPTION OF THE DRAWINGS erol, mannitol, diuretics, and the like are exemplified. How ever, a more effective therapeutic agent is required. 0011 FIG. 1 shows the effects of the anti-HMGB1 mono 0005 HMGB1, i.e. High Mobility Group box 1, is a pro clonal antibody which specifically binds to C-tail with neu tein in which 95% or more of amino acid sequence is equal tralizing the activity of HMGB1. FIG. 1(A) shows the levels from a rodent to a human. The HMGB1 is present in a normal of ICAM-1 expression on monocytes by addition of HMGB1, cell. However, the blood concentration thereof is increased by and FIG. 1 (B) shows the levels of ICAM-1 expression in case stimulation with LPS (liposaccharide) which is an endotoxin that the anti-HMGB1 monoclonal antibody is added simulta released in sepsis, one of systemic inflammatory response neously with addition of HMGB1. syndromes, leading to final tissue failure. Therefore, in the 0012 FIG. 2 shows the suppressing effects of administra technology described in Published Japanese Translation of tion of the anti-HMGB1 monoclonal antibody which specifi PCT International Publication No. 2003-520763, an HMG cally binds to C-tail on the increased permeability of brain antagonist is administered in order to treat a symptom having blood vessel. In non-ischemic group without load of cerebral a characteristic of activation of an inflammatory cytokine ischemia, leakage of Evans blue, i.e. dye, is not seen. On the cascade. However, there is neither description nor Suggestion other hand, in a control antibody-administered group to about not only cerebral edema but also general edema in the which cerebral ischemia was loaded and a control antibody publication. In addition, it is described in Published Japanese was administered, a considerable amount of leakage is Translation of PCT International Publication No. 2005 observed. In an anti-HMGB1 antibody-administered group to 512507 that the anti-HMGB1 antibody may treat a disease which the anti-HMGB1 monoclonal antibody of the present associated with an inflammatory cytokine cascade. However, invention was administered, such a leakage is clearly inhib the anti-HMGB1 antibody specifically binds to the box part ited. of HMGB1, and there is neither description nor suggestion 0013 FIG. 3 summarizes the quantitative comparison of about not only cerebral edema but also general edema in the the leakage of Evans blue into brain tissue between the con publication. trol antibody-administered group and the anti-HMGB1 anti 0006. In addition, it is described in Published Japanese body-administered group. It is found that the increased per Translation of PCT International Publication No. 2005 meability of brain blood vessels can be significantly inhibited 537253 that an HMGB1 antagonist such as anti-HMGB1 by administering the anti-HMGB1 monoclonal antibody. antibody is used for treating edema and the like. However, the 0014 FIG. 4 is a graph showing the relative amount of dye anti-HMGB1 antibody actually used in the publication is (Evans blue) which extravasated from microvasculature after antibodies which specifically bind to box or residues 166 to administration of saline, HMGB1 only, HMGB1+the anti US 2010/0172909 A1 Jul. 8, 2010 HMGB1 monoclonal antibody according to the present 0.2 to 2 mg/kg per dosage. However, the dose of the Suppres invention, or HMGB1+a monoclonal antibody binding to box sant should be suitably changed depending on patient's age, of HMGB1, to the dorsal skin of experimental rats. sex and severity of illness and the like. 0023. In the present invention method, the cerebral edema BEST MODE FOR CARRYING OUT THE Suppressant may be administered by intravenous injection. It INVENTION is at least experimentally demonstrated that the cerebral edema Suppressant according to the present invention can 0015. In the present invention method, the cerebral edema suppressant which contains the anti-HMGB1 monoclonal Suppress cerebral edema by intravenous injection, though it is antibody specifically binding to C-tail of HMGB1 as active unknown whether the Suppressant acts on brain blood vessel ingredients is administered. to inhibit the increased permeability or acts on brain cell 0016. The anti-HMGB1 monoclonal antibody according through the blood-brain barrier. to the present invention specifically binds to C-tail of 0024 Cerebral edema suppressant results from a number HMGB1 and neutralizes HMGB1, and inhibits the increased of causes. It is preferable to administer the cerebral edema permeability of brain blood vessel, to suppress cerebral Suppressant according to the present invention immediately edema. On the other hand, the antibody does not act on the after the cause of cerebral edema arises, since it becomes other parts of HMGB1 and other substances. Therefore, it is possible the Suppressant can prevent plasma proteins from considered that there is no or extremely little possibility of extravasating from brain blood vessel and can prevent the production of an adverse side effect.
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