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  Methods of treating lupus based on antibody affinity and screening methods and compositions for use thereofUSPTO Application #: 20060142229Title: Methods of treating lupus based on antibody affinity and screening methods and compositions for use thereof Abstract: The invention provides methods identifying individuals suitable for treatment for lupus and methods of monitoring treatment, based on measuring antibody affinities, as well as of treating lupus based on measuring antibody affinities. The treatment entails administration of a conjugate comprising a non-immunogenic valency platform molecule and at least two double stranded DNA epitopes, such as DNA molecules, which bind to anti-DNA antibodies from the patient. (end of abstract) Agent: Morrison & Foerster LLP - Palo Alto, CA, US Inventors: Matthew D. Linnik, Patricia A. McNeeley USPTO Applicaton #: 20060142229 - Class: 514044000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20060142229. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. provisional application Ser. No. 60/167,716, filed Nov. 28, 1999, which is incorporated by reference in its entirety. TECHNICAL FIELD [0002] This invention relates to the field of antibody-mediated pathologies such as lupus. More particularly, the invention relates to methods of treating individuals (and selecting individuals for treatment) for lupus based on antibody affinity. BACKGROUND ART [0003] Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies to a number of nuclear antigens, including double-stranded DNA (dsDNA). Autoantibodies that react with DNA are believed to play a role in the pathology of SLE and are closely associated with lupus nephritis. See, for example, Morimoto et al. (1982) J. Immunol. 139:1960-1965; Foster et al. (1993) Lab. Invest. 69:494-507; ter Borg et al. (1990) Arthritis Rheum. 33:634-643; Bootsma et al. (1995) Lancet 345:1595-1599. [0004] Synthetic double-stranded oligonucleotides (dsON) have been shown to cross-react with anti-dsDNA antibodies (U.S. Pat. No. 5,276,013). The use of dsON conjugated with non-immunogenic carriers, also referred to as platforms, has been proposed for a therapeutic approach for the treatment of SLE. For example, a tetrakis conjugate, LJP 249, composed of four dsON attached to a poly(ethylene glycol) valency platform was used to demonstrate tolerance in an immunized mouse model system (Jones et al. (1994) Bioconjugate Chem. 5:390-399). [0005] LJP 394, a tetravalent conjugate composed of four dsON attached to a platform, was shown to delay progression of renal disease and extend survival in the BXSB experimental murine lupus nephritis model (Plunkett et al. (1995) Lupus 4:S99; Coutts et al. (1996) Lupus 5:158-159). LJP 394 has also been shown to lower anti-dsDNA antibodies in human patients with SLE (Weisman et al. (1997) J Rheumatol. 24:314-318). [0006] Other literature describes methods which may be used in the treatment of SLE, including methods of reducing levels of circulating antibodies by inducing B cell tolerance, including, but not limited to, U.S. Pat. Nos. 5,276,013; 5,391,785; 5,786,512; 5,726,329; 5,552,391; 5,268,454; 5,606,047; 5,633,395; 5,162,515; U.S. Ser. No. 08/118,055 (U.S. Pat. No. 6,060,056); U.S. Ser. Nos. 60/088,656 and 60/103,088 (U.S. Ser. No. 09/328,199 and PCT App. No. PCT/US99/13194). [0007] Although overall patient prognosis in SLE has improved, treatment regimens are not ideal and lupus nephritis continues to be associated with relatively poor overall survival (Seleznick et al. (1991) Semin. Arthritis Rheum. 21:73-80). [0008] What is needed are improved methods of treatment of SLE and improved methods of identifying patients who may particularly respond to a given treatment. [0009] All references cited herein are hereby incorporated by reference in their entirety. DISCLOSURE OF THE INVENTION [0010] The invention provides methods relating to immunotolerance treatment of lupus based on assessment of initial affinity of antibody from the individual (i.e., antibody associated with lupus, namely, anti-ds DNA antibodies). The invention also provides methods of identifying individuals suitable (or unsuitable) for treatment based on assessing antibody affinity, as well as methods of treatment based on assessment of change of affinity (if any) upon receiving treatment. [0011] Accordingly, in one aspect, the invention provides methods of treating SLE (including lupus nephritis) in an individual, comprising administering to the individual a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more double stranded DNA epitopes, preferably polynucleotides, which specifically bind to an antibody from the individual which specifically binds to double stranded DNA, wherein affinity of the epitope, preferably polynucleotide, for the antibody from the individual is used as a basis for selecting the individual to receive the treatment. In other embodiments, the invention provides methods of treating SLE in an individual, comprising administering to the individual a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more double stranded DNA epitopes, preferably polynucleotides which specifically bind to an antibody from the individual which specifically binds to double stranded DNA, wherein affinity of the epitope, preferably polynucleotide, for the antibody from the individual is used as a basis for selecting the individual to continue to receive the treatment. [0012] As using affinity as a basis for selecting an individual suitable for treatment indicates, the treatment methods described herein generally entail measuring antibody affinity (of an individual's anti-double stranded DNA antibodies) for the dsDNA epitope. [0013] In another aspect, the invention provides methods of treating systemic lupus erythematosus (SLE) in an individual, comprising administering to the individual a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more polynucleotides which specifically bind to an antibody from the individual which specifically binds to double stranded DNA, said polynucleotide preferably comprising, consisting essentially of or consisting of the double stranded DNA sequence 5'-GTGTGTGTGTGTGTGTGTGT-3', wherein the apparent equilibrium dissociation constant (K.sub.D'), or its functional equivalent, for the polynucleotide with respect to the antibody from the individual before or upon initiation of treatment is less than about 1.0 mg IgG per ml, and wherein said K.sub.D' value (or its functional equivalent) is used as a basis for selecting the individual to receive the treatment. [0014] In some embodiments, the treatment methods also include a selection step comprising assessing before initiation of treatment an apparent equilibrium dissociation constant (K.sub.D') (or its functional equivalent) for the epitope, preferably a polynucleotide, contained within the conjugate with respect to antibodies from the individual which specifically bind to double stranded DNA, said conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more dsDNA epitopes which specifically bind to an antibody from the individual which specifically binds to double stranded DNA, wherein the individual is selected to receive the treatment if the K.sub.D' (or its functional equivalent) is less than about 1.0 mg IgG per ml. Other, lower K.sub.D' values are described herein which could apply to any of the dsDNA epitopes contemplated for use in treatment, as are percentile ranking with respect to a given patient population as described herein. Preferably, the dsDNA epitopes are polynucleotides, said polynucleotide preferably comprising, consisting essentially of or consisting of the double stranded DNA sequence 5'-GTGTGTGTGTGTGTGTGTGT-3'. [0015] In another aspect, the invention provides methods of treating SLE in an individual comprising: (a) assessing affinity of an anti-double stranded DNA antibody from the individual with respect to a dsDNA epitope which is to be used in treatment, wherein the individual is selected for treatment based on said antibody affinity; and (b) administering to said selected individual a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more of the dsDNA epitopes. [0016] In another aspect, the invention provides methods of treating lupus nephritis in an individual, comprising administering to the individual a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more polynucleotides which specifically bind to an antibody from the individual which specifically binds to double stranded DNA, said polynucleotide comprising, consisting essentially of, or consisting of the double stranded DNA sequence 5'-GTGTGTGTGTGTGTGTGTGT-3', wherein the apparent equilibrium dissociation constant (K.sub.D') (or its functional equivalent) for the polynucleotide in the conjugate with respect to the antibody from the individual before or upon initiation of treatment is less than about 1.0 mg IgG per ml, and wherein said K.sub.D' value (or its functional equivalent) is used as a basis for selecting the individual to receive the treatment. [0017] In another aspect, the invention provides methods of treating SLE in an individual, comprising: (a) assessing before or upon initiation of treatment an apparent equilibrium dissociation constant (K.sub.D') for a dsDNA epitope in or of a conjugate with respect to an antibody from the individual which specifically binds to double stranded DNA, said conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more said epitopes which specifically bind to an antibody from the individual which specifically binds to double stranded DNA and (b) administering to the individual the conjugate in an amount sufficient to increase the K.sub.D', wherein treatment is continued if K.sub.D' is increased at least about 20% compared to K.sub.D' before or upon initiation of treatment. In other embodiments, treatment methods comprise administering any of the conjugate(s) described herein in an amount sufficient to reduce the affinity as reflected by an affinity measurement (as, for example, reflected by increased K.sub.D'), preferably by at least about 20%, although greater changes may be desirable. [0018] In another aspect, the invention provides methods of treating lupus nephritis in an individual comprising administering to the individual a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more dsDNA epitopes which specifically bind to an antibody from the individual which specifically binds to double stranded DNA. In some embodiments, antibody affinity is assessed as described herein. In some embodiments, conjugate is administered in an amount sufficient to reduce antibody affinity. [0019] In another aspect, the invention provides methods of identifying an individual who may be suitable for treatment for SLE, said treatment comprising administration of a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more polynucleotides which specifically bind to an antibody from the individual which specifically binds to double stranded DNA, said polynucleotide comprising, consisting essentially of, or consisting of the dsDNA sequence 5'-GTGTGTGTGTGTGTGTGTGT-3', said method comprising measuring the apparent equilibrium dissociation constant (K.sub.D') or its functional equivalent for the polynucleotide used in the conjugate and anti-double stranded DNA antibodies from the individual before or upon initiation of treatment, wherein an individual is identified by K.sub.D' of less than about 1.0 mg IgG per ml or a functional equivalent thereof. [0020] In another aspect, the invention provides methods of identifying an individual who may be unsuitable for treatment for SLE, said treatment comprising administration of a conjugate comprising (a) a non-immunogenic valency platform molecule and (b) two or more polynucleotides which specifically bind to an antibody from the individual which specifically binds to double stranded DNA, said polynucleotide comprising, consisting essentially of, or consisting of the dsDNA sequence 5'-GTGTGTGTGTGTGTGTGTGT-3', said method comprising measuring the apparent equilibrium dissociation constant (K.sub.D') or its functional equivalent for the polynucleotide of the conjugate and anti-double stranded DNA antibodies from the individual before or upon initiation of treatment, wherein an individual is identified by K.sub.D' of more than about 1.0 mg IgG per ml or a functional equivalent thereof. Continue reading... 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