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(12) Patent Application Publication (10) Pub. No.: US 2011/0076344 A1 KUEHINE Et Al US 2011 0076344A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0076344 A1 KUEHINE et al. (43) Pub. Date: Mar. 31, 2011 (54) USE OF A CHEMICALLY-STABILIZED Publication Classification CHLORITESOLUTION FOR INHIBITING AN (51) Int. Cl. ANTIGEN-SPECIFIC MMUNE RESPONSE A633/20 (2006.01) (75) Inventors: Friedrich-W. KUEHNE, Bangkok A6IP 2L/04 (2006.01) (TH); Michael McGRATH, A6IP3/10 (2006.01) Burlingame, CA (US); Edgar A6IP 9/02 (2006.01) A6IPI/00 (2006.01) ENGLEMAN, Atherton, CA (US) A6IP 25/00 (2006.01) Assignee: DIMETHAIDAG, Friboug (CH) A6IP II/06 (2006.01) (73) A6IP II/00 (2006.01) (21) Appl. No.: 12/894,618 A6IP 700 (2006.01) (52) U.S. Cl. ........................................................ 424/661 (22) Filed: Sep. 30, 2010 (57) ABSTRACT Related U.S. Application Data Methods of using a stabilized chlorite solution to inhibit (63) Continuation of application No. 12/132,761, filed on antigen-specific immune responses are disclosed. The stabi Jun. 4, 2008, now abandoned, which is a continuation lized chlorite solution, when administered to a mammal in of application No. 10/895,941, filed on Jul. 22, 2004, need thereof, can prevent the presentation of antigens by now abandoned, which is a continuation of application antigen presenting cells. The Stabilized chlorite Solution No. 09/166,969, filed on Oct. 6, 1998, now abandoned. therefore is useful in treating, inter alia, auto-immune dis eases, treating diseases caused by an inappropriate immune (60) Provisional application No. 60/060,953, filed on Oct. response, treating lymphoproliferative disease and in inhib 6, 1997. iting rejection in transplant patients. Patent Application Publication Mar. 31, 2011 Sheet 1 of 12 US 2011/0076344 A1 ANTIGEN MACROPHAGEACTIVATED PRESENTATION MHCCLASS OO IMMUNE RESPONSE ANERGICRESPONSE ANTIGEN ACTIVATE PRESENTATION ACTIVATED MACROPHAGE MACROPHAGE MHCCLASS () () OO T-CEL T-CE CYTOKINE STIMULATION NOCYTOKINE STIMULATION F.G. 1 Patent Application Publication Mar. 31, 2011 Sheet 2 of 12 US 2011/0076344 A1 EFFECT OF WF10 ONDC STIMULATED ALLOGENECMLR 3OOOO 20000 - NONE -- WF1/200 -H WF1/400 -A- WF1/800 10000 - WF1/1600 O 1000 2000 3000 # DC/WELL FIG. 2 Patent Application Publication Mar. 31, 2011 Sheet 3 of 12 US 2011/0076344 A1 EFFECT OF WF10 ONMONOCYTESTIMULATED ALLOGENECMLR 10000 8000 NONE -- WF1/200 6000 -- WF1/400 -A- WF1/800 WF1/1600 4000 1000 2000 3000 # MONOCYTES/WELL FG. 3 Patent Application Publication Mar. 31, 2011 Sheet 4 of 12 US 2011/0076344 A1 EFFECT OF WF10 ON SOLUBLE ANTIGEN INDUCED PROLIFERATION (PRESENTED BY DC) 30000 NONE I WF1/200 WF1/800 20000 - L f He s ? OOOO - NONE TT KLH25 KLH.50 ANTIGEN FIG. 4 Patent Application Publication Mar. 31, 2011 Sheet 5 of 12 US 2011/0076344 A1 EFFECT OF WF10 ON SOLUBLE ANTIGEN INDUCED PROLIFERATION (PRESENTED MONOCYTES) 10000 NONE WF1/200 8000 WF1/400 WF/800 WF1/1600 6000 4000 2000 re NONE TT KLH25 KLH.50 ANTIGEN FIG. 5 Patent Application Publication Mar. 31, 2011 Sheet 6 of 12 US 2011/0076344 A1 s wer o ris" SE 2. A. ce ar st a s s f stse as - CO 3. as g CD -- 2 sease s S S t 92 ar 2. le 2 d waite 2 5 ar s as: o o o reme re (n/STO) +6900'+7.003 NIOS8v NVW Patent Application Publication Mar. 31, 2011 Sheet 7 of 12 US 2011/0076344 A1 n re C ve SE 2. f V Cee C- -X. re- ext - - al t - o CP N - Ce N 2 e hrt- yett am C5 f st unmarCA &R's C9 e L en 2. cN C He CD 2 c - l 2. o s 2 2. i write St. true ax s ne co se S Sg S s soma (INIST130)treas JNL'+p,003 LnIOSSYNVW Patent Application Publication Mar. 31, 2011 Sheet 8 of 12 US 2011/0076344 A1 ra st MRway o N. re e e e 9/2 Cre >- ? ne ; e- cy g ae saar' r . &. OO e as y a CD CX A. as: -- Ce - S. CD C - 2 O ill 25 2 e 2. aC qas s - ax a. (Cs co S S 3 ca s (INIST130) 9COO'+900'+ECOLNIOSSYNV3N Patent Application Publication Mar. 31, 2011 Sheet 9 of 12 US 2011/0076344 A1 s s c s SE 2. s errors s es est N C Cen C als al Y S s CD -- g stosis c & te 9 g near al i e e 2 e f e st s ra se o es s S s S s Se s were seas (inSTBO)4:00'-00031NOSav NWN Patent Application Publication Mar. 31, 2011 Sheet 10 of 12 US 2011/0076344 A1 s brer 2. t Se S. can S. -? E. S st eae as: e - 2 S. soax s S O ba C-e ra e - ala werwow awaa 2 Se CDEast. sO S (d CD CD as C 2. SC25 2 2. d A st e K P rooms s - a 2 48 5 ex e or ce ae o ach o ca quous (NSIBO) (LNOOldX3)xSON SISOLA009YHd 3 in IOSYNV3W Patent Application Publication Mar. 31, 2011 Sheet 11 of 12 US 2011/0076344 A1 N. st o ser pany N. - e c A. e Cem se d re- 8 - ass S ? ke. -g -str tra 1. 2. rea ca-- mor st SA CD C ce assage C) N L e N SC m 2 e d i. 2. sP 2 2. 5 sms s smas se sex ae ox a to go o co on god od to old to des at sh o or od r. cd a r or CN war e os ex N. ed ed. CN cra cra in en ca en cra cra N rear se sm (NISTIBO) +4O'+7.003 NIOSSV NVW Patent Application Publication Mar. 31, 2011 Sheet 12 of 12 US 2011/0076344 A1 PATIENTHH WITH SELBEFORE AND AFTER TREATMENT WITH WFO 30,06.98 14,0798 28,0798 108.98 25,0898 08.0998 22,0998 F.G. 12 US 2011/0076344 A1 Mar. 31, 2011 USE OF A CHEMICALLY-STABILIZED 0005. In the course of a normal immune response the TCR CHLORITESOLUTION FOR INHIBITING AN must first be capable of recognizing and binding to the antigen ANTIGEN-SPECIFIC IMMUNE RESPONSE presented. It is believed, however, that more than a simple binding of antigen is needed to bring about the cascade of CROSS-REFERENCE TO RELATED events described above. Thus, it is thought that a ligand APPLICATION present on the APC must react with a costimulatory receptor on the T cell to bring about lymphocyte activation. Specifi 0001. This application is a Continuation of U.S. patent cally, the B7 molecule on the surface of the APC interacts application Ser. No. 12/132,761, filed Jun. 4, 2008, which is a with its counterreceptor on the T cell, CD28, a molecule Continuation of U.S. patent application Ser. No. 10/895,941, which forms a part of the TCR. Siegel, et al., CLINICAL IMMU filed Jul. 22, 2004, which is a Continuation of U.S. patent NOLOGY, PRINCIPLES AND PRACTICE (RICH): "Signal Trans application Ser. No. 09/166,969, filed Oct. 6, 1998 (aban duction and T lymphocyte activation. Chpt. 12, pp 192-216, doned); which claims priority to U.S. Provisional Patent Mosby, St. Louis, Mo. (1996). See also Roitt, supra at pp. Application No. 60/060,953 filed Oct. 6, 1997, the entire 169-17O. specification, claims, and drawings of which are incorporated 0006. One of the strongest immune responses is termed an herewith by reference. allogeneic response, which involves the immune system reacting against non-self MHC alloantigens. This type of FIELD OF THE INVENTION reactivity is observed, for example, in rejection of non-self 0002 The present invention relates to the use of a stabi grafts, such as transplanted organs, and clearly is undesirable lized chlorite solution to inhibit antigen-specific immune in Such situations. Reported mechanisms of immunosuppres responses. The stabilized chlorite solution inhibits antigen sion that act by interfering with allorecognition (i.e., by specific immune responses by impeding antigen presentation depletion of graft antigen, inhibition of APC function, block by antigen presenting cells. The stabilized chlorite Solution ade of Surface receptor/co-receptor molecules, etc.) are inef therefore is useful in treating diseases caused by or associated fective for preventing or reducing the severity of analogeneic with unwanted or inappropriate antigen-specific immune response, however, because of their toxic side effects and responses including, for example, auto-immune diseases, their short-term activity. RICH supra., at “Concepts and chal hepatitis B and C, chronic hepatitis, chronic obstructive pull lenges in solid organ transplantation. Chpt. 104, pp. 1593 monary disease, systemic lupus erythemotosus and in pre 1607. In addition, there are no reported treatment regimens venting rejection in organ transplant and graft patients (graft that are effective in blocking the B7/CD28 co-stimulatory versus host disease). The stabilized chlorite solution also is interaction. useful in treating lymphoma, specifically, follicular non 0007. The immune system of most mammals is capable of Hodgkin's lymphoma. recognizing and responding to self and foreign antigens in an appropriate manner. The phenomenon where the immune system does not respond to self-antigens is termed immuno BACKGROUND OF THE INVENTION logical tolerance. Triplett, J. Immunol. 86: 505-510, (1962). 0003. A feature common to an immune response is the Tolerance to self antigens sometimes breaks down, however, recognition of an antigen (either foreign or self, but perceived causing autoimmunity, where Tor B cells (or both), as well as as foreign), and Subsequent processing by the immune sys various cytokines of a mammal, react against and destroy the tem.
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